Neuroscience Center at Dartmouth

Dartmouth, Lebanon

Neuroscience Center at Dartmouth

Dartmouth, Lebanon
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Hernan A.E.,Neuroscience Center at Dartmouth | Holmes G.L.,Neuroscience Center at Dartmouth | Isaev D.,Neuroscience Center at Dartmouth | Isaev D.,State Key Laboratory for Molecular and Cellular Biology | And 4 more authors.
Neurobiology of Disease | Year: 2013

Seizures during development are a relatively common occurrence and are often associated with poor cognitive outcomes. Recent studies show that early life seizures alter the function of various brain structures and have long-term consequences on seizure susceptibility and behavioral regulation. While many neocortical functions could be disrupted by epileptic seizures, we have concentrated on studying the prefrontal cortex (PFC) as disturbance of PFC functions is involved in numerous co-morbid disorders associated with epilepsy. In the present work we report an alteration of short-term plasticity in the PFC in rats that have experienced early life seizures. The most robust alteration occurs in the layer II/III to layer V network of neurons. However short-term plasticity of layer V to layer V network was also affected, indicating that the PFC function is broadly influenced by early life seizures. These data strongly suggest that repetitive seizures early in development cause substantial alteration in PFC function, which may be an important component underlying cognitive deficits in individuals with a history of seizures during development. © 2012 Elsevier Inc.


Bender A.C.,Neuroscience Center at Dartmouth | Natola H.,Neuroscience Center at Dartmouth | Ndong C.,Neuroscience Center at Dartmouth | Holmes G.L.,Neuroscience Center at Dartmouth | And 3 more authors.
Neurobiology of Disease | Year: 2013

Cognitive impairment is a common comorbidity in pediatric epilepsy that can severely affect quality of life. In many cases, antiepileptic treatments fail to improve cognition. Therefore, a fundamental question is whether underlying brain abnormalities may contribute to cognitive impairment through mechanisms independent of seizures. Here, we examined the possible effects on cognition of Nav1.1 down-regulation, a sodium channel principally involved in Dravet syndrome but also implicated in other cognitive disorders, including autism and Alzheimer's disease. Using an siRNA approach to knockdown Nav1.1 selectively in the basal forebrain region, we were able to target a learning and memory network while avoiding the generation of spontaneous seizures. We show that reduction of Nav1.1 expression in the medial septum and diagonal band of Broca leads to a dysregulation of hippocampal oscillations in association with a spatial memory deficit. We propose that the underlying etiology responsible for Dravet syndrome may directly contribute to cognitive impairment in a manner that is independent from seizures. © 2013 Elsevier Inc.


Duffy B.A.,University College London | Choy M.,University of California at Irvine | Riegler J.,University College London | Riegler J.,Center for Mathematics and Physics in the Life science and Experimental Biology | And 5 more authors.
NeuroImage | Year: 2012

Early inflammation following status epilepticus has been implicated in the development of epilepsy and the evolution of brain injury, yet its precise role remains unclear. The development of non-invasive imaging markers of inflammation would enable researchers to test this hypothesis in vivo and study its temporal progression in relation to epileptogenic insults. In this study we have investigated the potential of a targeted magnetic resonance imaging contrast agent - vascular cell adhesion molecule 1 antibody labelled iron oxide - to image the inflammatory process following status epilepticus in the rat lithium-pilocarpine model. Intravascular administration of the targeted contrast agent was performed at approximately 1day following status epilepticus. The control group received diazepam prior to pilocarpine to prevent status epilepticus. Magnetic resonance imaging of rats was performed before and after contrast administration. Comparison with quantitative T 2 measurements was also performed. At the end of the study, brains were removed for ex vivo magnetic resonance imaging and histology. Marked focal hypointensities caused by contrast agent binding were observed on in vivo magnetic resonance images in the post status epilepticus group. In particular these occurred in the periventricular organs, the hippocampus and the cerebral cortex. Relatively little contrast agent binding was observed in the control group. T 2 relaxation times were not significantly increased for the hippocampus or the cerebral cortex in post status epilepticus animals. These results demonstrate the feasibility of in vivo imaging of seizure-induced inflammation in an animal model of epilepsy. The antibody targeted MRI contrast agent identified regions of acute inflammation following status epilepticus and may provide an early marker of brain injury. This technique could be used to determine the role of inflammation in models of epileptogenesis and to study the potential for anti-inflammatory therapeutic interventions. © 2012 Elsevier Inc.


Kleen J.K.,Neuroscience Center at Dartmouth | Wu E.X.,Neuroscience Center at Dartmouth | Holmes G.L.,Neuroscience Center at Dartmouth | Scott R.C.,Neuroscience Center at Dartmouth | And 2 more authors.
Journal of Neuroscience | Year: 2011

Neurological insults during development are associated with later impairments in learning and memory. Although remedial training can help restore cognitive function, the neural mechanisms of this recovery in memory systems are largely unknown. To examine this issue, we measured electrophysiological oscillatory activity in the hippocampus (both CA3 and CA1) and prefrontal cortex of adult rats that had experienced repeated seizures in the first weeks of life, while they were remedially trained on a delayed-nonmatch-to-sample memory task. Seizure-exposed rats showed initial difficulties learning the task but performed similarly to control rats after extra training. Whole-session analyses illustrated enhanced theta power in all three structures while seizure rats learned response tasks before the memory task. While performing the memory task, dynamic oscillation patterns revealed that prefrontal cortex theta power was increased among seizure-exposed rats. This enhancement appeared after the first memory-training steps using short delays and plateaued at the most difficult steps, which included both short and long delays. Further, seizure rats showed enhanced CA1-prefrontal cortex theta coherence in correct trials compared with incorrect trials when long delays were imposed, suggesting increased hippocampal-prefrontal cortex synchrony for the task in this group when memory demand was high. Seizure-exposed rats also showed heightened gamma power and coherence among all three structures during the trials. Our results demonstrate the first evidence of hippocampal-prefrontal enhancements following seizures in early development. Dynamic compensatory changes in this network and interconnected circuitsmay underpin cognitive rehabilitation following other neurological insults to higher cognitive systems. © 2011 the authors.


Jacobs V.L.,Neuroscience Center at Dartmouth | de Leo J.A.,Neuroscience Center at Dartmouth | de Leo J.A.,Emmanuel College at Boston
PLoS ONE | Year: 2012

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain cancer, with a median survival of less than 2 years after diagnosis with current available therapies. The tumor microenvironment serves a critical role in tumor invasion and progression, with microglia as a critical player. Our laboratory has previously demonstrated that propentofylline, an atypical methylxanthine with central nervous system glial modulating and anti-inflammatory actions, significantly decreases tumor growth in a GBM rodent model by preferentially targeting microglia. In the present study, we used the CNS-1 rat glioma model to elucidate the mechanisms of propentofylline. Here we demonstrate that propentofylline targets TROY, a novel signaling molecule up-regulated in infiltrating microglia, and not macrophages, in response to CNS-1 cells. We identify Pyk2, Rac1 and pJNK as the downstream signaling molecules of TROY through western blot analysis and siRNA transfection. We demonstrate that inhibition of TROY expression in microglia by siRNA transfection significantly inhibits microglial migration towards CNS-1 cells similar to 10 μM propentofylline treatment. These results identify TROY as a novel molecule expressed in microglia, involved in their migration and targeted by propentofylline. Furthermore, these results describe a signaling molecule that is differentially expressed between microglia and macrophages in the tumor microenvironment. © 2012 Jacobs et al.


Khan O.I.,Neuroscience Center at Dartmouth | Zhao Q.,Neuroscience Center at Dartmouth | Miller F.,Neuroscience Center at Dartmouth | Holmes G.L.,Neuroscience Center at Dartmouth
Neurobiology of Disease | Year: 2010

Frequent interictal spikes are a common finding in the electroencephalograms of children with epileptic encephalopathies. While it is well recognized that interictal spikes are a biological marker of seizures and can lead to transitory cognitive impairment, whether interictal spikes can result in long-standing adverse effects on learning and memory in children is not known. Here we investigated the consequences of interictal spikes in rat pups without seizures on long-term learning and memory. Rat pups were given a low dose of flurothyl for 4h for 10 days during continuous electroencephalographic monitoring. Rats developed interictal spikes without seizures while age-matched controls under similar testing conditions had few interictal spikes. When rats were tested as adults, there was impairment in reference memory in the probe test of the Morris water maze, reference memory impairment in the four-trial radial-arm water maze and impaired long-term potentiation. Early-life interictal spikes resulted in impaired new cell formation and decreased cell counts in the hippocampus but did not cause an increase in apoptosis. This study, for the first time demonstrates that interictal spikes in rat pups without seizures can result in long-standing spatial cognitive impairment. Our findings suggest that suppressing IIS may be as important as treating seizures during brain development. © 2010 Elsevier Inc.


Isaeva E.,Neuroscience Center at Dartmouth | Isaeva E.,Bogomoletz Institute of Physiology | Hernan A.,Neuroscience Center at Dartmouth | Isaev D.,Neuroscience Center at Dartmouth | And 2 more authors.
Annals of Neurology | Year: 2012

Objective: An epileptic seizure is frequently the presenting sign of intracerebral hemorrhage (ICH) caused by stroke, head trauma, hypertension, and a wide spectrum of disorders. However, the cellular mechanisms responsible for occurrence of seizures during ICH have not been established. During intracerebral bleeding, blood constituents enter the neuronal tissue and produce both an acute and a delayed effect on brain functioning. Among the blood components, only thrombin has been shown to evoke seizures immediately after entering brain tissue. In the present study, we tested the hypothesis that thrombin increases neuronal excitability in the immature brain through alteration of voltage-gated sodium channels. Methods: The thrombin effect on neuronal excitability and voltage-gated sodium channels was assessed using extracellular and intracellular recording techniques in the hippocampal slice preparation of immature rats. Results: We show that thrombin increased neuronal excitability in the immature hippocampus in an N-methyl-D-aspartate-independent manner. Application of thrombin did not alter transient voltage-gated sodium channels and action potential threshold. However, thrombin significantly depolarized the membrane potential and produced a hyperpolarizing shift of tetrodotoxin-sensitive persistent voltage-gated sodium channel activation. This effect of thrombin was attenuated by application of protease-activated receptor-1 and protein kinase C antagonists. Interpretation: Our data indicate that thrombin amplifies the persistent voltage-gated sodium current affecting resting membrane potential and seizure threshold at the network level. Our results provide a novel explanation as to how ICH in newborns results in seizures, which may provide avenues for therapeutic intervention in the prevention of post-ICH seizures. Copyright © 2012 American Neurological Association.


Holmes G.L.,Neuroscience Center at Dartmouth
Epilepsia | Year: 2013

Cognitive impairment is a common and often devastating comorbidity of pharmacoresistent epilepsy. The cognitive comorbidity can be both chronic, primarily due to the underlying etiology of the epilepsy, and dynamic or evolving because of recurrent seizures or interictal spikes. There is now considerable evidence that interictal spikes can contribute to cognitive impairment. Interictal spikes in both rodents and humans result in transient impairment of memory retrieval, whereas in immature animals, interictal spikes can result in long-term adverse effects on brain development. Interictal spikes therefore contribute to the cognitive impairment in the pharmacoresistant epilepsies. Effective treatment of pharmacoresistant epilepsy needs to target not only the overt seizures but interictal electroencephalography (EEG) abnormalities as well. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.


Kulandaivel K.,Neuroscience Center at Dartmouth | Holmes G.L.,Neuroscience Center at Dartmouth
Epilepsy and Behavior | Year: 2011

There is increasing evidence that there is a strong relationship between brain oscillations and neurocognitive function. We used EEG power spectral analysis to determine if frequency and power provide an independent measure of developmental impairment in infants. We examined the spectral power of EEGs in 200 infants between 6 and 24. months of age who were evaluated for seizures. Infants were stratified into three age groups 6-12, 12-18, and 18-24. months, and development assessments were coded as normal, moderately delayed, and severely delayed. Compared with the normal infants, children with developmental delay had lower mean frequencies and greater delta and less theta and alpha power. Delta/theta and theta/alpha ratios were highly significant indicators of developmental status. This study demonstrates that frequency and power of brain oscillations during wakefulness is a strong predictor of development in infants. The findings support the concept that normal oscillatory activity is critical for normal cognitive function during development. © 2011 Elsevier Inc.


Kleen J.K.,Neuroscience Center at Dartmouth | Scott R.C.,Neuroscience Center at Dartmouth | Scott R.C.,University College London | Holmes G.L.,Neuroscience Center at Dartmouth | Lenck-Santini P.P.,Neuroscience Center at Dartmouth
Annals of Neurology | Year: 2010

Objective: Cognitive impairment is common in epilepsy, particularly in memory function. Interictal spikes (IISs) are thought to disrupt cognition, but it is difficult to delineate their contribution from general impairments in memory produced by etiology and seizures. We investigated the transient impact of focal IISs on the hippocampus, a structure crucial for learning and memory and yet highly prone to IISs in temporal lobe epilepsy (TLE). Methods: Bilateral hippocampal depth electrodes were implanted into 14 Sprague-Dawley rats, followed by intrahippocampal pilocarpine or saline infusion unilaterally. Rats that developed chronic spikes were trained in a hippocampal-dependent operant behavior task, delayed-match-to-sample. Depth-electroencephalogram (EEG) was recorded during 5,562 trials among five rats, and within-subject analyses evaluated the impact of hippocampal spikes on short-term memory operations. Results: Hippocampal spikes that occurred during memory retrieval strongly impaired performance (p < 0.001). However, spikes that occurred during memory encoding or memory maintenance did not affect performance in those trials. Hippocampal spikes also affected response latency, adding approximately 0.48 seconds to the time taken to respond (p < 0.001). Interpretation: We found that focal IIS-related interference in cognition extends to structures in the limbic system, which required intrahippocampal recordings. Hippocampal spikes seem most harmful if they occur when hippocampal function is critical, extending human studies showing that cortical spikes are most disruptive during active cortical functioning. The cumulative effects of spikes could therefore impact general cognitive functioning. These results strengthen the argument that suppression of IISs may improve memory and cognitive performance in patients with epilepsy. © 2010 American Neurological Association.

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