Lisa Gabel - Profile on Academia.edu (original) (raw)
Papers by Lisa Gabel
Journal of Neurophysiology, Apr 1, 1998
Neostriatal spiny projection neurons can display a is manifested as a slowing of the rate of depo... more Neostriatal spiny projection neurons can display a is manifested as a slowing of the rate of depolarization giving pronounced delay in their transition to action potential discharge rise to a subthreshold ramp potential that can last for hunthat is mediated by a slowly developing ramp depolarization. The dreds of milliseconds. When the depolarizing input is mainpossible contribution of a slowly inactivating A-type K / current tained, the ramp potential eventually will culminate in action lar concentrations of 4-AP, further supporting a role for these A distinctive electrophysiological property of spiny procurrents in the mediating this response (McCormick 1991; jection neurons within the neostriatum is their ability to at-Storm 1988). tenuate the amplitude of voltage transients evoked by sub-Voltage-clamp recording experiments from neostriatal spiny neurons have shown that these cells possess at least threshold depolarizing current pulses
Brain Research, May 1, 2011
Abnormal development of the neocortex is often associated with cognitive deficits and epilepsy. R... more Abnormal development of the neocortex is often associated with cognitive deficits and epilepsy. Rodent models are widely used to study normal and abnormal cortical development and have revealed the roles of many important genetic and environmental factors. Interestingly, several inbred mouse strains commonly used in behavioral, anatomical, and/or physiological studies display neocortical malformations including C57BL/6J mice, which are among the most widely utilized mice. In the present report we describe the prevalence and cytoarchitecture of molecular-layer heterotopia in C57BL/6J mice and related strains obtained from three commercial vendors as well as mice bred in academic vivaria from founders obtained commercially. In particular, we found that the prevalence of molecular-layer heterotopia vaired according to the sex as well as the vendorof-origin of the mouse. These data are relevant to the use of this strain as a mouse-model in the study of brain-behavior relationships.
Journal of Neurophysiology, Mar 1, 1999
Cholinergic regulation of striatal spiny projection neuron activity is predominantly mediated thr... more Cholinergic regulation of striatal spiny projection neuron activity is predominantly mediated through muscarinic receptor modulation of several subclasses of ion channels. Because of its critical role in governing the recurring episodes of hyperpolarization and depolarization characteristic of spiny neurons in vivo, the 4-aminopyridine-resistant, persistent potassium (K ϩ ) current, I Krp , would be a strategic target for modulation. The present results show that I Krp can be either suppressed or enhanced by muscarinic receptor stimulation. Biophysical analysis demonstrated that the depression of I Krp was associated with a hyperpolarizing shift in the voltage dependence of inactivation and a reduction in maximal conductance. By contrast, the enhancement of I Krp was linked to hyperpolarizing shifts in both activation and inactivation voltage dependencies. Viewed in the context of the natural activity of spiny neurons, muscarinic depression of I Krp should uniformly increase excitability in both hyperpolarized and depolarized states. In the hyperpolarized state, the reduction in maximal conductance should bolster the efficacy of impending excitatory input. Likewise, in the depolarized state, the decreased availability of I Krp produced by the shift in inactivation should enhance ongoing synaptic input. The alterations associated with enhancement of I Krp are predicted to have a more dynamic influence on spiny cell excitability. In the hyperpolarized state, the negative shift in activation should increase the flow of I Krp and attenuate subsequent excitatory synpatic input; whereas once the cell has traversed into the depolarized state, the negative shift in inactivation should reduce the availability of this current and diminish its influence on the existing excitatory barrage.
Brain Research, Mar 1, 2011
Focal cortical dysplasia (FCD) are associated with neurological disorders and cognitive impairmen... more Focal cortical dysplasia (FCD) are associated with neurological disorders and cognitive impairments in humans. Molecular layer ectopia, clusters of misplaced cells in layer I of the neocortex, have been identified in patients with developmental dyslexia and psychomotor retardation. Mouse models of this developmental disorder display behavioral impairments and increased seizure susceptibility. Although there is a correlation between cortical malformations and neurological dysfunction, little is known about the morphological and physiological properties of cells within cortical malformations. In the present study we used electrophysiological and immunocytochemical analyses to examine the distribution of neuronal and non-neuronal cell types within and surrounding layer I neocortical ectopia in NXSMD/EiJ mice. We show that cells within ectopia have membrane properties of both pyramidal and a variety of non-pyramidal cell types, including fast-spiking cells. Immunocytochemical analysis for different interneuronal subtypes demonstrates that ectopia contain nonpyramidal cells immunoreactive for calbindin-D28K (CALB), parvalbumin (PARV), and calretinin (CR). Ectopia also contains astrocytes, positive for glial fibrillary acidic protein (GFAP) and oligodendrocyte precursor cells positive for NG2 proteoglycan (NG2). Lastly, we provide electrophysiological and morphological evidence to demonstrate that cells within ectopia receive input from cells within layers I, upper and deeper II/III, and V and provide outputs to cells within deep layer II/III and layer V, but not layers I and upper II/III. These results indicate that ectopia contain cells of different lineages with diverse morphological and physiological properties, and appear to cause disruptions in local cortical circuitry.
Cellular properties, cortical circuitry and aberrant activity associated with focal neocortical dysplasias
Cortical malformations have been associated with cognitive impairments and epilepsy in humans. Se... more Cortical malformations have been associated with cognitive impairments and epilepsy in humans. Several animal models of cortical dysplasia show that dysplasia causes increased seizure susceptibility and behavioral deficits in vivo, and increased levels of excitability in vitro. Small groups of displaced neurons in layer I of the neocortex, ectopias, have been identified in patients with cognitive impairments, and similar malformations occur sporadically in some inbred lines of mice where they are associated with behavioral and sensory processing deficits. Although there is a correlation between cortical malformations and neurological impairments the particular properties of dysplastic cortex that cause impaired function have not been clearly defined. Before we can examine potential causes of impaired function we first need to understand the cellular properties of ectopias. Electrophysiological and histological analysis revealed that neurons within ectopias display multiple types of action potential filing patterns, and morphological properties, including pyramidal and a variety of nonpyramidal cells. Ectopic cells have glutamatergic and GABAergic synapses, and receive direct excitatory and inhibitory input from adjacent normatopic cortex. Further examination of intracortical circuitry in slices containing ectopias reveal that although ectopic cells receive input from cells in all cortical layers of the normatopic cortex, they only send projections to neurons within deep cortical layers. Despite normal physiological properties of ectopic cells, aberrant activity was evident. Spontaneous epileptiform activity was shown to occur when multiple adjacent ectopias were present in a single slice. Using extracellular recordings from brain slices we show that even single layer I ectopias are associated with higher excitability. Specifically, slices that contain single ectopias display epileptiform activity at significantly lower concentrations of bicuculline than do slices without ectopias. We demonstrate that this enhanced excitability is not generated within ectopias, since removal of ectopias from slices does not restore normal excitability. Examination of seizure susceptibility in vivo showed that mice with ectopias are more sensitive to the convulsant pentylenetetrazole than are mice without ectopias These results suggest that alterations in slices containing ectopias increase cortical excitability in vitro and in vivo . In its entirety, the findings in this thesis enhance our understanding of cortical maldevelopment and the consequences of cortically dysplasia on neurological function.
Journal of Neurophysiology, 1999
Muscarinic receptors differentially modulate the persistent potassium current in striatal spiny p... more Muscarinic receptors differentially modulate the persistent potassium current in striatal spiny projection neurons. Cholinergic regulation of striatal spiny projection neuron activity is predominantly mediated through muscarinic receptor modulation of several subclasses of ion channels. Because of its critical role in governing the recurring episodes of hyperpolarization and depolarization characteristic of spiny neurons in vivo, the 4-aminopyridine–resistant, persistent potassium (K+) current, I Krp, would be a strategic target for modulation. The present results show that I Krp can be either suppressed or enhanced by muscarinic receptor stimulation. Biophysical analysis demonstrated that the depression of I Krp was associated with a hyperpolarizing shift in the voltage dependence of inactivation and a reduction in maximal conductance. By contrast, the enhancement of I Krp was linked to hyperpolarizing shifts in both activation and inactivation voltage dependencies. Viewed in the c...
Journal of Neurophysiology, 1998
Gabel, Lisa A. and Eric S. Nisenbaum. Biophysical characterization and functional consequences of... more Gabel, Lisa A. and Eric S. Nisenbaum. Biophysical characterization and functional consequences of a slowly inactivating potassium current in neostriatal neurons. J. Neurophysiol. 79: 1989–2002, 1998. Neostriatal spiny projection neurons can display a pronounced delay in their transition to action potential discharge that is mediated by a slowly developing ramp depolarization. The possible contribution of a slowly inactivating A-type K+ current ( I As) to this delayed excitation was investigated by studying the biophysical and functional properties of I As using whole cell voltage- and current-clamp recording from acutely isolated neostriatal neurons. Isolation of I As from other voltage-gated, calcium-independent K+ currents was achieved through selective blockade of I As with low concentrations (10 μM) of the benzazepine derivative,6 - chloro - 7 , 8 - dihydroxy - 3 - allyl - 1 - phenyl - 2 , 3 , 4 , 5 - tetra - hydro1H-3-benzazepine (APB; SKF82958) and subsequent current subtracti...
Cellular properties, cortical circuitry and aberrant activity associated with focal neocortical dysplasias
Cortical malformations have been associated with cognitive impairments and epilepsy in humans. Se... more Cortical malformations have been associated with cognitive impairments and epilepsy in humans. Several animal models of cortical dysplasia show that dysplasia causes increased seizure susceptibility and behavioral deficits in vivo, and increased levels of excitability in vitro. Small groups of displaced neurons in layer I of the neocortex, ectopias, have been identified in patients with cognitive impairments, and similar malformations occur sporadically in some inbred lines of mice where they are associated with behavioral and sensory processing deficits. Although there is a correlation between cortical malformations and neurological impairments the particular properties of dysplastic cortex that cause impaired function have not been clearly defined. Before we can examine potential causes of impaired function we first need to understand the cellular properties of ectopias. Electrophysiological and histological analysis revealed that neurons within ectopias display multiple types of action potential filing patterns, and morphological properties, including pyramidal and a variety of nonpyramidal cells. Ectopic cells have glutamatergic and GABAergic synapses, and receive direct excitatory and inhibitory input from adjacent normatopic cortex. Further examination of intracortical circuitry in slices containing ectopias reveal that although ectopic cells receive input from cells in all cortical layers of the normatopic cortex, they only send projections to neurons within deep cortical layers. Despite normal physiological properties of ectopic cells, aberrant activity was evident. Spontaneous epileptiform activity was shown to occur when multiple adjacent ectopias were present in a single slice. Using extracellular recordings from brain slices we show that even single layer I ectopias are associated with higher excitability. Specifically, slices that contain single ectopias display epileptiform activity at significantly lower concentrations of bicuculline than do slices without ectopias. We demonstrate that this enhanced excitability is not generated within ectopias, since removal of ectopias from slices does not restore normal excitability. Examination of seizure susceptibility in vivo showed that mice with ectopias are more sensitive to the convulsant pentylenetetrazole than are mice without ectopias These results suggest that alterations in slices containing ectopias increase cortical excitability in vitro and in vivo . In its entirety, the findings in this thesis enhance our understanding of cortical maldevelopment and the consequences of cortically dysplasia on neurological function.
Spontaneous seizures in the flathead (fh/fh) mutant are associated with altered interneuron number and function
Neuroreport, 2001
Utilizing rodent models, prior research has demonstrated a signi®cant association between focal n... more Utilizing rodent models, prior research has demonstrated a signi®cant association between focal neocortical malformations (i.e. induced microgyria, molecular layer ectopias), which are histologically similar to those observed in human dyslexic brains, and rate-speci®c auditory processing de®cits as seen in language impaired populations. In the current study, we found that ectopic NZB/BINJ mice exhibit signi®cant impairments in detecting a variable duration 5.6 kHz tone embedded in a 10.5 kHz continuous background, using both acoustic re¯ex modi®cation and auditory event-related potentials (AERP). The current results add further support to the association between focal cortical malformations and impaired auditory processing, and the notion that these auditory effects may occur regardless of the cortical location of the anomaly. NeuroReport 12:2875± 2879 & 2001 Lippincott Williams & Wilkins.
Brain Research, 2011
Abnormal development of the neocortex is often associated with cognitive deficits and epilepsy. R... more Abnormal development of the neocortex is often associated with cognitive deficits and epilepsy. Rodent models are widely used to study normal and abnormal cortical development and have revealed the roles of many important genetic and environmental factors. Interestingly, several inbred mouse strains commonly used in behavioral, anatomical, and/or physiological studies display neocortical malformations including C57BL/6J mice, which are among the most widely utilized mice. In the present report we describe the prevalence and cytoarchitecture of molecular-layer heterotopia in C57BL/6J mice and related strains obtained from three commercial vendors as well as mice bred in academic vivaria from founders obtained commercially. In particular, we found that the prevalence of molecular-layer heterotopia vaired according to the sex as well as the vendorof-origin of the mouse. These data are relevant to the use of this strain as a mouse-model in the study of brain-behavior relationships.
Brain Research, 2011
Focal cortical dysplasia (FCD) are associated with neurological disorders and cognitive impairmen... more Focal cortical dysplasia (FCD) are associated with neurological disorders and cognitive impairments in humans. Molecular layer ectopia, clusters of misplaced cells in layer I of the neocortex, have been identified in patients with developmental dyslexia and psychomotor retardation. Mouse models of this developmental disorder display behavioral impairments and increased seizure susceptibility. Although there is a correlation between cortical malformations and neurological dysfunction, little is known about the morphological and physiological properties of cells within cortical malformations. In the present study we used electrophysiological and immunocytochemical analyses to examine the distribution of neuronal and non-neuronal cell types within and surrounding layer I neocortical ectopia in NXSMD/EiJ mice. We show that cells within ectopia have membrane properties of both pyramidal and a variety of non-pyramidal cell types, including fast-spiking cells. Immunocytochemical analysis for different interneuronal subtypes demonstrates that ectopia contain nonpyramidal cells immunoreactive for calbindin-D28K (CALB), parvalbumin (PARV), and calretinin (CR). Ectopia also contains astrocytes, positive for glial fibrillary acidic protein (GFAP) and oligodendrocyte precursor cells positive for NG2 proteoglycan (NG2). Lastly, we provide electrophysiological and morphological evidence to demonstrate that cells within ectopia receive input from cells within layers I, upper and deeper II/III, and V and provide outputs to cells within deep layer II/III and layer V, but not layers I and upper II/III. These results indicate that ectopia contain cells of different lineages with diverse morphological and physiological properties, and appear to cause disruptions in local cortical circuitry.
Biotechnology Progress, 2003
In an attempt to integrate biological components with silicon-based devices and systems, artifici... more In an attempt to integrate biological components with silicon-based devices and systems, artificial silane surfaces have been successfully used to grow motoneurons in a defined environment. In this study we characterized the morphology and electrophysiology of purified rat embryonic (E14) motoneurons grown on a selfassembled monolayer (SAM) of N-1 [3-(trimethoxysilyl)propyl]diethylenetriamine (DETA) versus that on ornithine/laminin surfaces in serum-free media. On DETA motoneurons were flat and grew more processes, whereas on ornithine/laminin they tended to aggregate. The membrane time constant, a characteristic associated with electrotonic compactness, was significantly longer for motoneurons grown on DETA. Other electrophysiological parameters were similar for the motoneurons on the different surfaces. This is the first study where purified ventral horn motoneurons were cultured in a completely defined (nonbiological surface, serum-free) environment.
The Journal of Neuroscience, 2004
Fragile X syndrome is the most common form of inherited mental retardation and is caused by the l... more Fragile X syndrome is the most common form of inherited mental retardation and is caused by the loss of function of the Fragile X mental retardation protein (FMRP). FMRP is an RNA binding protein thought to play a key role in protein synthesis-dependent synaptic plasticity. The regulation of FMRP expression itself is also likely to be an important control point in this process. Here we used dark-reared/light-exposed rats to determine the role of experience in regulating FMRP levels in the visual cortex. We find that FMRP levels increase in the cell bodies and dendrites of visual cortical neurons after as little as 15 min of light exposure. Remarkably, FMRP expression in these neurons returns to baseline levels by 30 min of light exposure. These changes were post-transcriptional because the FMR1 mRNA levels remained constant over this time period. A transient increase in FMRP levels was also observed in synaptic fractions prepared from visual cortices of light-exposed animals. In con...
Journal of Neurophysiology, Feb 1, 2001
Focal developmental abnormalities in neocortex, including ectopic collections of neurons in layer... more Focal developmental abnormalities in neocortex, including ectopic collections of neurons in layer I (ectopias), have been associated with behavioral and neurological deficits. In this study, we used infrared differential interference contrast microscopy and whole cell patch-clamp to complete the first characterization of neurons within and surrounding neocortical ectopias. Current-clamp recordings revealed that neurons within ectopias display multiple types of action potential firing patterns, and biocytin labeling indicated that ϳ20% of the cells in neocortical ectopias can be classified as nonpyramidal cells and the rest as atypically oriented pyramidal cells. All cells had spontaneous excitatory (glutamatergic) and inhibitory (GABAergic) postsynaptic currents. Exhibitory postsynaptic currents consisted of both N-methyl-D-aspartate (NMDA) receptor-mediated and AMPA/kainate (A/K) receptor-mediated currents. The NMDA receptor-mediated component had decay time constants of 15.35 Ϯ 2.2 (SE) ms, while the A/K component had faster decay kinetics of 7.6 Ϯ 1.7 ms at Ϫ20 mV. GABA A receptormediated synaptic currents in ectopic cells reversed at potentials near the Cl Ϫ equilibrium potential and had decay kinetics of 16.65 Ϯ 1.3 ms at 0 mV. Furthermore we show that cells within ectopias receive direct excitatory and inhibitory input from adjacent normatopic cortex and can display a form of epileptiform activity.
P300-based brain-computer interface memory game to improve motivation and performance
ABSTRACT A brain-computer interface (BCI) relies on a classifier to determine a user's in... more ABSTRACT A brain-computer interface (BCI) relies on a classifier to determine a user's intent through the EEG signals. This classifier needs to be trained with a specific user prior to its usage. Since the effectiveness of a classifier is affected by the user's motivation during training, a memory game using the BCPy2000 platform has been developed for enhancing motivation and performance in using a traditional P300-based BCI system. A pilot study showed that this memory game is accomplishable by human subjects in a BCI system.
Developmental Neuroscience
Reading disability (RD), which affects between 5 and 17% of the population worldwide, is the most... more Reading disability (RD), which affects between 5 and 17% of the population worldwide, is the most prevalent form of learning disability, and is associated with underactivation of a universal reading network in children. However, recent research suggests there are differences in learning rates on cognitive predictors of reading performance, as well as differences in activation patterns within the reading neural network, based on orthographic depth (i.e., transparent/shallow vs. deep/opaque orthographies) in children with RD. Recently, we showed that native English-speaking children with RD exhibit impaired performance on a maze learning task that taps into the same neural networks that are activated during reading. In addition, we demonstrated that genetic risk for RD strengthens the relationship between reading impairment and maze learning performance. However, it is unclear whether the results from these studies can be broadly applied to children from other language orthographies. ...
Design of an Affordable Brain-Computer Interface for Robot Navigation
2019 14th IEEE Conference on Industrial Electronics and Applications (ICIEA)
Brain-computer interface (BCI) devices are designed to bypass neuromuscular pathways enabling an ... more Brain-computer interface (BCI) devices are designed to bypass neuromuscular pathways enabling an individual to operate an external device using neural activity, as opposed to motor activity. Neural outputs are detected and utilized to drive a command signal to control a device, such as a wheelchair. BCIs provide individuals with severe motor impairment with an alternative mechanism to interact with their environment. Ultimately BCIs help to restore some degree of autonomy to an individual with limited motor control. Increased autonomy will likely lead to an enhanced quality of life of the individual as well as the caregiver(s). In this paper, we developed a BCI-controlled, ground-based robot. A wireless EEG headset was used to obtain the EEG signals from the user and stream the signals wirelessly into a host computer. The computer processed the EEG signals, extracted possible features from the signals to interpret the user's intents as the control commands, and then sent the command signals wirelessly to navigate the robot. This paper discusses the methodology used in the design as well as the response speed and accuracy in robot navigation from the test results. Future applications in assistive technology by using similar design concept are also discussed.
Developmental Neuroscience
Dyslexia is a common learning disability that affects processing of written language despite adeq... more Dyslexia is a common learning disability that affects processing of written language despite adequate intelligence and educational background. If learning disabilities remain untreated, a child may experience long-term social and emotional problems, which influence future success in all aspects of their life. Dyslexia has a 60% heritability rate, and genetic studies have identified multiple dyslexia susceptibility genes (DSGs). DSGs, such as DCDC2, are consistently associated with the risk and severity of reading disability (RD). Altered neural connectivity within temporoparietal regions of the brain is associated with specific variants of DSGs in individuals with RD. Genetically altering DSG expression in mice results in visual and auditory processing deficits as well as neurophysiological and neuroanatomical disruptions. Previously, we demonstrated that learning deficits associated with RD can be translated across species using virtual environments. In this 2-year longitudinal stu...
Classification Predictive Modeling of Dyslexia
2022 56th Annual Conference on Information Sciences and Systems (CISS)
Dyslexia is a reading disability that affects children across language orthographies, despite ade... more Dyslexia is a reading disability that affects children across language orthographies, despite adequate intelligence and educational opportunity. If learning disabilities remain untreated, a child may experience long-term social and emotional problems, which may influence future success in all aspects of their lives. Early detection and intervention will help to close the gap between typically developing and reading impaired children in acquiring reading skills. We have demonstrated that animal models of dyslexia, genetic models based on candidate dyslexia susceptibility genes, and children with specific reading impairment show a common deficit on a virtual Hebb-Williams maze task. Since virtual maze task does not require oral reporting (rapid access to phonological processing) or rely on text, performance is not influenced by a potential difference in reading experience between groups. Although the correlation between dyslexia and the performance in the virtual Hebb-Williams maze task has been demonstrated, classification of atypical participants (i.e., dyslexic participants) through real-time observation of their performance on the virtual Hebb-Williams maze task is not feasible at this time. A computational model based on machine learning algorithms, that can predict reading ability based on maze learning performance, would enable real-time feedback of the performance in the form of at-risk percentages for reading. This paper presents the preliminary results of employing machine-learning based computational models to classify virtual maze performance on this task. Reading data and maze learning outcomes were analyzed from 227 school-aged children (8–14 years of age). Applying multiple variables, such as age and biological sex, into machine learning algorithms resulted in the prediction accuracy above 70%. Successful development of this predictive model would allow for early detection of risk for reading impairment, which can lead to early interventions to close the gap between typically developing and reading impaired children in acquiring reading skills.
Journal of Neurophysiology, Apr 1, 1998
Neostriatal spiny projection neurons can display a is manifested as a slowing of the rate of depo... more Neostriatal spiny projection neurons can display a is manifested as a slowing of the rate of depolarization giving pronounced delay in their transition to action potential discharge rise to a subthreshold ramp potential that can last for hunthat is mediated by a slowly developing ramp depolarization. The dreds of milliseconds. When the depolarizing input is mainpossible contribution of a slowly inactivating A-type K / current tained, the ramp potential eventually will culminate in action lar concentrations of 4-AP, further supporting a role for these A distinctive electrophysiological property of spiny procurrents in the mediating this response (McCormick 1991; jection neurons within the neostriatum is their ability to at-Storm 1988). tenuate the amplitude of voltage transients evoked by sub-Voltage-clamp recording experiments from neostriatal spiny neurons have shown that these cells possess at least threshold depolarizing current pulses
Brain Research, May 1, 2011
Abnormal development of the neocortex is often associated with cognitive deficits and epilepsy. R... more Abnormal development of the neocortex is often associated with cognitive deficits and epilepsy. Rodent models are widely used to study normal and abnormal cortical development and have revealed the roles of many important genetic and environmental factors. Interestingly, several inbred mouse strains commonly used in behavioral, anatomical, and/or physiological studies display neocortical malformations including C57BL/6J mice, which are among the most widely utilized mice. In the present report we describe the prevalence and cytoarchitecture of molecular-layer heterotopia in C57BL/6J mice and related strains obtained from three commercial vendors as well as mice bred in academic vivaria from founders obtained commercially. In particular, we found that the prevalence of molecular-layer heterotopia vaired according to the sex as well as the vendorof-origin of the mouse. These data are relevant to the use of this strain as a mouse-model in the study of brain-behavior relationships.
Journal of Neurophysiology, Mar 1, 1999
Cholinergic regulation of striatal spiny projection neuron activity is predominantly mediated thr... more Cholinergic regulation of striatal spiny projection neuron activity is predominantly mediated through muscarinic receptor modulation of several subclasses of ion channels. Because of its critical role in governing the recurring episodes of hyperpolarization and depolarization characteristic of spiny neurons in vivo, the 4-aminopyridine-resistant, persistent potassium (K ϩ ) current, I Krp , would be a strategic target for modulation. The present results show that I Krp can be either suppressed or enhanced by muscarinic receptor stimulation. Biophysical analysis demonstrated that the depression of I Krp was associated with a hyperpolarizing shift in the voltage dependence of inactivation and a reduction in maximal conductance. By contrast, the enhancement of I Krp was linked to hyperpolarizing shifts in both activation and inactivation voltage dependencies. Viewed in the context of the natural activity of spiny neurons, muscarinic depression of I Krp should uniformly increase excitability in both hyperpolarized and depolarized states. In the hyperpolarized state, the reduction in maximal conductance should bolster the efficacy of impending excitatory input. Likewise, in the depolarized state, the decreased availability of I Krp produced by the shift in inactivation should enhance ongoing synaptic input. The alterations associated with enhancement of I Krp are predicted to have a more dynamic influence on spiny cell excitability. In the hyperpolarized state, the negative shift in activation should increase the flow of I Krp and attenuate subsequent excitatory synpatic input; whereas once the cell has traversed into the depolarized state, the negative shift in inactivation should reduce the availability of this current and diminish its influence on the existing excitatory barrage.
Brain Research, Mar 1, 2011
Focal cortical dysplasia (FCD) are associated with neurological disorders and cognitive impairmen... more Focal cortical dysplasia (FCD) are associated with neurological disorders and cognitive impairments in humans. Molecular layer ectopia, clusters of misplaced cells in layer I of the neocortex, have been identified in patients with developmental dyslexia and psychomotor retardation. Mouse models of this developmental disorder display behavioral impairments and increased seizure susceptibility. Although there is a correlation between cortical malformations and neurological dysfunction, little is known about the morphological and physiological properties of cells within cortical malformations. In the present study we used electrophysiological and immunocytochemical analyses to examine the distribution of neuronal and non-neuronal cell types within and surrounding layer I neocortical ectopia in NXSMD/EiJ mice. We show that cells within ectopia have membrane properties of both pyramidal and a variety of non-pyramidal cell types, including fast-spiking cells. Immunocytochemical analysis for different interneuronal subtypes demonstrates that ectopia contain nonpyramidal cells immunoreactive for calbindin-D28K (CALB), parvalbumin (PARV), and calretinin (CR). Ectopia also contains astrocytes, positive for glial fibrillary acidic protein (GFAP) and oligodendrocyte precursor cells positive for NG2 proteoglycan (NG2). Lastly, we provide electrophysiological and morphological evidence to demonstrate that cells within ectopia receive input from cells within layers I, upper and deeper II/III, and V and provide outputs to cells within deep layer II/III and layer V, but not layers I and upper II/III. These results indicate that ectopia contain cells of different lineages with diverse morphological and physiological properties, and appear to cause disruptions in local cortical circuitry.
Cellular properties, cortical circuitry and aberrant activity associated with focal neocortical dysplasias
Cortical malformations have been associated with cognitive impairments and epilepsy in humans. Se... more Cortical malformations have been associated with cognitive impairments and epilepsy in humans. Several animal models of cortical dysplasia show that dysplasia causes increased seizure susceptibility and behavioral deficits in vivo, and increased levels of excitability in vitro. Small groups of displaced neurons in layer I of the neocortex, ectopias, have been identified in patients with cognitive impairments, and similar malformations occur sporadically in some inbred lines of mice where they are associated with behavioral and sensory processing deficits. Although there is a correlation between cortical malformations and neurological impairments the particular properties of dysplastic cortex that cause impaired function have not been clearly defined. Before we can examine potential causes of impaired function we first need to understand the cellular properties of ectopias. Electrophysiological and histological analysis revealed that neurons within ectopias display multiple types of action potential filing patterns, and morphological properties, including pyramidal and a variety of nonpyramidal cells. Ectopic cells have glutamatergic and GABAergic synapses, and receive direct excitatory and inhibitory input from adjacent normatopic cortex. Further examination of intracortical circuitry in slices containing ectopias reveal that although ectopic cells receive input from cells in all cortical layers of the normatopic cortex, they only send projections to neurons within deep cortical layers. Despite normal physiological properties of ectopic cells, aberrant activity was evident. Spontaneous epileptiform activity was shown to occur when multiple adjacent ectopias were present in a single slice. Using extracellular recordings from brain slices we show that even single layer I ectopias are associated with higher excitability. Specifically, slices that contain single ectopias display epileptiform activity at significantly lower concentrations of bicuculline than do slices without ectopias. We demonstrate that this enhanced excitability is not generated within ectopias, since removal of ectopias from slices does not restore normal excitability. Examination of seizure susceptibility in vivo showed that mice with ectopias are more sensitive to the convulsant pentylenetetrazole than are mice without ectopias These results suggest that alterations in slices containing ectopias increase cortical excitability in vitro and in vivo . In its entirety, the findings in this thesis enhance our understanding of cortical maldevelopment and the consequences of cortically dysplasia on neurological function.
Journal of Neurophysiology, 1999
Muscarinic receptors differentially modulate the persistent potassium current in striatal spiny p... more Muscarinic receptors differentially modulate the persistent potassium current in striatal spiny projection neurons. Cholinergic regulation of striatal spiny projection neuron activity is predominantly mediated through muscarinic receptor modulation of several subclasses of ion channels. Because of its critical role in governing the recurring episodes of hyperpolarization and depolarization characteristic of spiny neurons in vivo, the 4-aminopyridine–resistant, persistent potassium (K+) current, I Krp, would be a strategic target for modulation. The present results show that I Krp can be either suppressed or enhanced by muscarinic receptor stimulation. Biophysical analysis demonstrated that the depression of I Krp was associated with a hyperpolarizing shift in the voltage dependence of inactivation and a reduction in maximal conductance. By contrast, the enhancement of I Krp was linked to hyperpolarizing shifts in both activation and inactivation voltage dependencies. Viewed in the c...
Journal of Neurophysiology, 1998
Gabel, Lisa A. and Eric S. Nisenbaum. Biophysical characterization and functional consequences of... more Gabel, Lisa A. and Eric S. Nisenbaum. Biophysical characterization and functional consequences of a slowly inactivating potassium current in neostriatal neurons. J. Neurophysiol. 79: 1989–2002, 1998. Neostriatal spiny projection neurons can display a pronounced delay in their transition to action potential discharge that is mediated by a slowly developing ramp depolarization. The possible contribution of a slowly inactivating A-type K+ current ( I As) to this delayed excitation was investigated by studying the biophysical and functional properties of I As using whole cell voltage- and current-clamp recording from acutely isolated neostriatal neurons. Isolation of I As from other voltage-gated, calcium-independent K+ currents was achieved through selective blockade of I As with low concentrations (10 μM) of the benzazepine derivative,6 - chloro - 7 , 8 - dihydroxy - 3 - allyl - 1 - phenyl - 2 , 3 , 4 , 5 - tetra - hydro1H-3-benzazepine (APB; SKF82958) and subsequent current subtracti...
Cellular properties, cortical circuitry and aberrant activity associated with focal neocortical dysplasias
Cortical malformations have been associated with cognitive impairments and epilepsy in humans. Se... more Cortical malformations have been associated with cognitive impairments and epilepsy in humans. Several animal models of cortical dysplasia show that dysplasia causes increased seizure susceptibility and behavioral deficits in vivo, and increased levels of excitability in vitro. Small groups of displaced neurons in layer I of the neocortex, ectopias, have been identified in patients with cognitive impairments, and similar malformations occur sporadically in some inbred lines of mice where they are associated with behavioral and sensory processing deficits. Although there is a correlation between cortical malformations and neurological impairments the particular properties of dysplastic cortex that cause impaired function have not been clearly defined. Before we can examine potential causes of impaired function we first need to understand the cellular properties of ectopias. Electrophysiological and histological analysis revealed that neurons within ectopias display multiple types of action potential filing patterns, and morphological properties, including pyramidal and a variety of nonpyramidal cells. Ectopic cells have glutamatergic and GABAergic synapses, and receive direct excitatory and inhibitory input from adjacent normatopic cortex. Further examination of intracortical circuitry in slices containing ectopias reveal that although ectopic cells receive input from cells in all cortical layers of the normatopic cortex, they only send projections to neurons within deep cortical layers. Despite normal physiological properties of ectopic cells, aberrant activity was evident. Spontaneous epileptiform activity was shown to occur when multiple adjacent ectopias were present in a single slice. Using extracellular recordings from brain slices we show that even single layer I ectopias are associated with higher excitability. Specifically, slices that contain single ectopias display epileptiform activity at significantly lower concentrations of bicuculline than do slices without ectopias. We demonstrate that this enhanced excitability is not generated within ectopias, since removal of ectopias from slices does not restore normal excitability. Examination of seizure susceptibility in vivo showed that mice with ectopias are more sensitive to the convulsant pentylenetetrazole than are mice without ectopias These results suggest that alterations in slices containing ectopias increase cortical excitability in vitro and in vivo . In its entirety, the findings in this thesis enhance our understanding of cortical maldevelopment and the consequences of cortically dysplasia on neurological function.
Spontaneous seizures in the flathead (fh/fh) mutant are associated with altered interneuron number and function
Neuroreport, 2001
Utilizing rodent models, prior research has demonstrated a signi®cant association between focal n... more Utilizing rodent models, prior research has demonstrated a signi®cant association between focal neocortical malformations (i.e. induced microgyria, molecular layer ectopias), which are histologically similar to those observed in human dyslexic brains, and rate-speci®c auditory processing de®cits as seen in language impaired populations. In the current study, we found that ectopic NZB/BINJ mice exhibit signi®cant impairments in detecting a variable duration 5.6 kHz tone embedded in a 10.5 kHz continuous background, using both acoustic re¯ex modi®cation and auditory event-related potentials (AERP). The current results add further support to the association between focal cortical malformations and impaired auditory processing, and the notion that these auditory effects may occur regardless of the cortical location of the anomaly. NeuroReport 12:2875± 2879 & 2001 Lippincott Williams & Wilkins.
Brain Research, 2011
Abnormal development of the neocortex is often associated with cognitive deficits and epilepsy. R... more Abnormal development of the neocortex is often associated with cognitive deficits and epilepsy. Rodent models are widely used to study normal and abnormal cortical development and have revealed the roles of many important genetic and environmental factors. Interestingly, several inbred mouse strains commonly used in behavioral, anatomical, and/or physiological studies display neocortical malformations including C57BL/6J mice, which are among the most widely utilized mice. In the present report we describe the prevalence and cytoarchitecture of molecular-layer heterotopia in C57BL/6J mice and related strains obtained from three commercial vendors as well as mice bred in academic vivaria from founders obtained commercially. In particular, we found that the prevalence of molecular-layer heterotopia vaired according to the sex as well as the vendorof-origin of the mouse. These data are relevant to the use of this strain as a mouse-model in the study of brain-behavior relationships.
Brain Research, 2011
Focal cortical dysplasia (FCD) are associated with neurological disorders and cognitive impairmen... more Focal cortical dysplasia (FCD) are associated with neurological disorders and cognitive impairments in humans. Molecular layer ectopia, clusters of misplaced cells in layer I of the neocortex, have been identified in patients with developmental dyslexia and psychomotor retardation. Mouse models of this developmental disorder display behavioral impairments and increased seizure susceptibility. Although there is a correlation between cortical malformations and neurological dysfunction, little is known about the morphological and physiological properties of cells within cortical malformations. In the present study we used electrophysiological and immunocytochemical analyses to examine the distribution of neuronal and non-neuronal cell types within and surrounding layer I neocortical ectopia in NXSMD/EiJ mice. We show that cells within ectopia have membrane properties of both pyramidal and a variety of non-pyramidal cell types, including fast-spiking cells. Immunocytochemical analysis for different interneuronal subtypes demonstrates that ectopia contain nonpyramidal cells immunoreactive for calbindin-D28K (CALB), parvalbumin (PARV), and calretinin (CR). Ectopia also contains astrocytes, positive for glial fibrillary acidic protein (GFAP) and oligodendrocyte precursor cells positive for NG2 proteoglycan (NG2). Lastly, we provide electrophysiological and morphological evidence to demonstrate that cells within ectopia receive input from cells within layers I, upper and deeper II/III, and V and provide outputs to cells within deep layer II/III and layer V, but not layers I and upper II/III. These results indicate that ectopia contain cells of different lineages with diverse morphological and physiological properties, and appear to cause disruptions in local cortical circuitry.
Biotechnology Progress, 2003
In an attempt to integrate biological components with silicon-based devices and systems, artifici... more In an attempt to integrate biological components with silicon-based devices and systems, artificial silane surfaces have been successfully used to grow motoneurons in a defined environment. In this study we characterized the morphology and electrophysiology of purified rat embryonic (E14) motoneurons grown on a selfassembled monolayer (SAM) of N-1 [3-(trimethoxysilyl)propyl]diethylenetriamine (DETA) versus that on ornithine/laminin surfaces in serum-free media. On DETA motoneurons were flat and grew more processes, whereas on ornithine/laminin they tended to aggregate. The membrane time constant, a characteristic associated with electrotonic compactness, was significantly longer for motoneurons grown on DETA. Other electrophysiological parameters were similar for the motoneurons on the different surfaces. This is the first study where purified ventral horn motoneurons were cultured in a completely defined (nonbiological surface, serum-free) environment.
The Journal of Neuroscience, 2004
Fragile X syndrome is the most common form of inherited mental retardation and is caused by the l... more Fragile X syndrome is the most common form of inherited mental retardation and is caused by the loss of function of the Fragile X mental retardation protein (FMRP). FMRP is an RNA binding protein thought to play a key role in protein synthesis-dependent synaptic plasticity. The regulation of FMRP expression itself is also likely to be an important control point in this process. Here we used dark-reared/light-exposed rats to determine the role of experience in regulating FMRP levels in the visual cortex. We find that FMRP levels increase in the cell bodies and dendrites of visual cortical neurons after as little as 15 min of light exposure. Remarkably, FMRP expression in these neurons returns to baseline levels by 30 min of light exposure. These changes were post-transcriptional because the FMR1 mRNA levels remained constant over this time period. A transient increase in FMRP levels was also observed in synaptic fractions prepared from visual cortices of light-exposed animals. In con...
Journal of Neurophysiology, Feb 1, 2001
Focal developmental abnormalities in neocortex, including ectopic collections of neurons in layer... more Focal developmental abnormalities in neocortex, including ectopic collections of neurons in layer I (ectopias), have been associated with behavioral and neurological deficits. In this study, we used infrared differential interference contrast microscopy and whole cell patch-clamp to complete the first characterization of neurons within and surrounding neocortical ectopias. Current-clamp recordings revealed that neurons within ectopias display multiple types of action potential firing patterns, and biocytin labeling indicated that ϳ20% of the cells in neocortical ectopias can be classified as nonpyramidal cells and the rest as atypically oriented pyramidal cells. All cells had spontaneous excitatory (glutamatergic) and inhibitory (GABAergic) postsynaptic currents. Exhibitory postsynaptic currents consisted of both N-methyl-D-aspartate (NMDA) receptor-mediated and AMPA/kainate (A/K) receptor-mediated currents. The NMDA receptor-mediated component had decay time constants of 15.35 Ϯ 2.2 (SE) ms, while the A/K component had faster decay kinetics of 7.6 Ϯ 1.7 ms at Ϫ20 mV. GABA A receptormediated synaptic currents in ectopic cells reversed at potentials near the Cl Ϫ equilibrium potential and had decay kinetics of 16.65 Ϯ 1.3 ms at 0 mV. Furthermore we show that cells within ectopias receive direct excitatory and inhibitory input from adjacent normatopic cortex and can display a form of epileptiform activity.
P300-based brain-computer interface memory game to improve motivation and performance
ABSTRACT A brain-computer interface (BCI) relies on a classifier to determine a user's in... more ABSTRACT A brain-computer interface (BCI) relies on a classifier to determine a user's intent through the EEG signals. This classifier needs to be trained with a specific user prior to its usage. Since the effectiveness of a classifier is affected by the user's motivation during training, a memory game using the BCPy2000 platform has been developed for enhancing motivation and performance in using a traditional P300-based BCI system. A pilot study showed that this memory game is accomplishable by human subjects in a BCI system.
Developmental Neuroscience
Reading disability (RD), which affects between 5 and 17% of the population worldwide, is the most... more Reading disability (RD), which affects between 5 and 17% of the population worldwide, is the most prevalent form of learning disability, and is associated with underactivation of a universal reading network in children. However, recent research suggests there are differences in learning rates on cognitive predictors of reading performance, as well as differences in activation patterns within the reading neural network, based on orthographic depth (i.e., transparent/shallow vs. deep/opaque orthographies) in children with RD. Recently, we showed that native English-speaking children with RD exhibit impaired performance on a maze learning task that taps into the same neural networks that are activated during reading. In addition, we demonstrated that genetic risk for RD strengthens the relationship between reading impairment and maze learning performance. However, it is unclear whether the results from these studies can be broadly applied to children from other language orthographies. ...
Design of an Affordable Brain-Computer Interface for Robot Navigation
2019 14th IEEE Conference on Industrial Electronics and Applications (ICIEA)
Brain-computer interface (BCI) devices are designed to bypass neuromuscular pathways enabling an ... more Brain-computer interface (BCI) devices are designed to bypass neuromuscular pathways enabling an individual to operate an external device using neural activity, as opposed to motor activity. Neural outputs are detected and utilized to drive a command signal to control a device, such as a wheelchair. BCIs provide individuals with severe motor impairment with an alternative mechanism to interact with their environment. Ultimately BCIs help to restore some degree of autonomy to an individual with limited motor control. Increased autonomy will likely lead to an enhanced quality of life of the individual as well as the caregiver(s). In this paper, we developed a BCI-controlled, ground-based robot. A wireless EEG headset was used to obtain the EEG signals from the user and stream the signals wirelessly into a host computer. The computer processed the EEG signals, extracted possible features from the signals to interpret the user's intents as the control commands, and then sent the command signals wirelessly to navigate the robot. This paper discusses the methodology used in the design as well as the response speed and accuracy in robot navigation from the test results. Future applications in assistive technology by using similar design concept are also discussed.
Developmental Neuroscience
Dyslexia is a common learning disability that affects processing of written language despite adeq... more Dyslexia is a common learning disability that affects processing of written language despite adequate intelligence and educational background. If learning disabilities remain untreated, a child may experience long-term social and emotional problems, which influence future success in all aspects of their life. Dyslexia has a 60% heritability rate, and genetic studies have identified multiple dyslexia susceptibility genes (DSGs). DSGs, such as DCDC2, are consistently associated with the risk and severity of reading disability (RD). Altered neural connectivity within temporoparietal regions of the brain is associated with specific variants of DSGs in individuals with RD. Genetically altering DSG expression in mice results in visual and auditory processing deficits as well as neurophysiological and neuroanatomical disruptions. Previously, we demonstrated that learning deficits associated with RD can be translated across species using virtual environments. In this 2-year longitudinal stu...
Classification Predictive Modeling of Dyslexia
2022 56th Annual Conference on Information Sciences and Systems (CISS)
Dyslexia is a reading disability that affects children across language orthographies, despite ade... more Dyslexia is a reading disability that affects children across language orthographies, despite adequate intelligence and educational opportunity. If learning disabilities remain untreated, a child may experience long-term social and emotional problems, which may influence future success in all aspects of their lives. Early detection and intervention will help to close the gap between typically developing and reading impaired children in acquiring reading skills. We have demonstrated that animal models of dyslexia, genetic models based on candidate dyslexia susceptibility genes, and children with specific reading impairment show a common deficit on a virtual Hebb-Williams maze task. Since virtual maze task does not require oral reporting (rapid access to phonological processing) or rely on text, performance is not influenced by a potential difference in reading experience between groups. Although the correlation between dyslexia and the performance in the virtual Hebb-Williams maze task has been demonstrated, classification of atypical participants (i.e., dyslexic participants) through real-time observation of their performance on the virtual Hebb-Williams maze task is not feasible at this time. A computational model based on machine learning algorithms, that can predict reading ability based on maze learning performance, would enable real-time feedback of the performance in the form of at-risk percentages for reading. This paper presents the preliminary results of employing machine-learning based computational models to classify virtual maze performance on this task. Reading data and maze learning outcomes were analyzed from 227 school-aged children (8–14 years of age). Applying multiple variables, such as age and biological sex, into machine learning algorithms resulted in the prediction accuracy above 70%. Successful development of this predictive model would allow for early detection of risk for reading impairment, which can lead to early interventions to close the gap between typically developing and reading impaired children in acquiring reading skills.