Publications by authors named "Dan C McIntyre"

29 Publications

  • Page 1 of 1

Prefrontal neuronal morphology in kindling-prone (FAST) and kindling-resistant (SLOW) rats.

Synapse 2021 Sep 6;75(9):e22217. Epub 2021 Jul 6.

Department of Neuroscience, University of Lethbridge, Lethbridge, Alberta, Canada.

The epileptogenic-prone (FAST) and epileptogenic-resistant (SLOW) rat strains have become a valuable tool for investigating neural plasticity. The strains were generated by breeding the rats that required the fewest amygdala stimulations to elicit a stage-5 convulsive seizure (FAST) and rats requiring the most stimulations (SLOW). Previous studies have shown differences in behavior and amygdala physiology in the two strains. This study examined the dendritic morphology of pyramidal neurons in the brains of adult male and female rats of the two strains. The brains were stained with the Golgi-Cox method and the length and branching from layer III pyramidal cells were measured in parietal cortex (Zilles Par1), medial frontal cortex (Zilles Cg3), and orbitofrontal cortex (Zilles AID) in these two strains of rats. We observed significantly longer dendrites in Cg3 in the FAST group but longer dendrites in the SLOW group in AID and Par1. There was also a sex difference (M > F) in Par1 in both strains. These morphological differences can provide insights into the neurobiological basis of the behavioral differences and suggest that localized changes in the amygdala do not occur independently of changes in other brain regions, and especially prefrontal cortex.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/syn.22217DOI Listing
September 2021

Relation between startle reactivity and sucrose avidity in two rat strains bred for differential seizure susceptibility.

Exp Neurol 2011 Jun 12;229(2):259-63. Epub 2011 Feb 12.

Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada K1S 5B6.

Rat strains selectively bred to be seizure-prone (Fast) versus seizure-resistant (Slow) show differing levels of anxiety, with Slow rats displaying relatively enhanced anxiety-like behaviors to aversive stimuli. Ample data has suggested that highly anxious rodents exhibit reduced avidity for sucrose and greater startle responses than rodents with relatively low anxiety levels. Thus, it was hypothesized that the Slow rats would have lower appetitive (sucrose consumption) and greater defensive (startle response) behaviors than Fast rats. Results confirmed that Slow rats consumed significantly less sucrose and exhibited greater acoustic startle responses than Fast rats. Startle response magnitude was not associated with water consumption, food consumption or body weight but was negatively correlated with sucrose consumption. These observations attest to the link between sucrose avidity and startle reactivity and further reveal that genetic selection for amygdala excitability lead to strain differences in appetitive and defensive behaviors. Thus, Fast and Slow rats may be two unique strains with which to further elucidate the genetic and neurobiological mechanisms underlying appetitive and defensive behaviors and their relation to anxiety and seizure sensitivity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.expneurol.2011.02.006DOI Listing
June 2011

Caloric restriction alters seizure disposition and behavioral profiles in seizure-prone (fast) versus seizure-resistant (slow) rats.

Behav Neurosci 2010 Feb;124(1):106-114

Institute of Neuroscience, Life Sciences Research Center, Carleton University.

Caloric restriction (CR), primarily known for extending life span, has proven anticonvulsant in several seizure models and antiepileptogenic in a strain of inherently seizure susceptible mice. Our animal model consisted of a seizure-prone (Fast) strain that naturally exhibits attention-deficit/hyperactivity disorder (ADHD)-like behaviors and a comparison seizure-resistant (Slow) strain; we evaluated CR's effect on the typical seizure sensitivities and behavioral profiles of each strain. Fast and Slow rats were fed ad libitum or were calorically restricted to 80% of free-feeding body weight. Rats were then tested in the open field (hyperactivity), Morris water maze (learning and attention), and restraint (impulsivity) paradigms and finally kindled from the amygdala. Ultimately, CR abolished signs of abnormal hyperactivity in the Fast strain and retarded their kindling rates, making it the first manipulation to demonstrate an antiepileptogenic effect in this animal model. CR also shortened seizure durations in fully kindled Slow rats but had no effect on their kindling rates, implying a differential effect of CR on genotype. These results clearly endorse further investigation into the potential benefits of CR for both epilepsy and ADHD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1037/a0018307DOI Listing
February 2010

Kindling as a model of human epilepsy.

Can J Neurol Sci 2009 Aug;36 Suppl 2:S33-5

Department of Psychology, Institute of Neuroscience, Carleton University, Ottawa, Ontario, Canada.

The evidence supporting the suggestion that kindling is a good model of human temporal lobe epilepsy is briefly reviewed. Parallels between the human condition, involving both partial and secondarily generalized seizures, and kindling in rats and other animals are drawn and contrasted.
View Article and Find Full Text PDF

Download full-text PDF

Source
August 2009

Postnatal epigenetic influences on seizure susceptibility in seizure-prone versus seizure-resistant rat strains.

Behav Neurosci 2009 Apr;123(2):337-46

Institute of Neuroscience, Life Sciences Research Center, Carleton University, Ottawa, Ontario, K1S 5B6, Canada.

The creation of seizure-prone (Fast) and seizure-resistant (Slow) rat strains via selective breeding implies genetic control of relative seizure vulnerability, yet ample data also advocates an environmental contribution. To investigate potential environmental underpinnings to the differential seizure sensitivities in these strains, the authors compared amygdala kindling profiles in adult male Fast and Slow rats raised by (a) their own mother, (b) a foster mother from the same strain, or (c) a foster mother from the opposing strain. Ultimately, strain-specific kindling profiles were not normalized by cross-fostering. Instead, both strains became more seizure-prone regardless of maternal affiliation (i.e., cross-fostered groups from both strains kindled faster than uncrossed controls). Interhemispheric seizure spread was also facilitated in cross-fostered Slow rat groups and was associated with increased commissural cross-sectional areas, giving them a Fast-like profile. It is important to note, however, that all Fast groups remained significantly more seizure-prone than Slow groups, suggesting that although the postnatal environment strongly influenced seizure disposition in both strains, it did not wholly account for their relative dispositions. Investigation into mechanisms fundamental to cross-fostering-induced seizure facilitation should help prevent postnatal worsening of pathology in already seizure-prone individuals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1037/a0014730DOI Listing
April 2009

Assessment of anxiety-like behaviors in female rats bred for differences in kindling susceptibility and amygdala excitability.

Brain Res 2008 Nov 12;1240:143-52. Epub 2008 Sep 12.

Department of Psychology, Institute of Neuroscience, Life Sciences Research Building Carleton University, Ottawa, Ontario, Canada.

Two rat lines bred for kindling susceptibility were previously observed to engage in different behavioral strategies in tests of emotionality. In order to extend past research on defensive behaviors in these strains which largely used males, Fast- and Slow-kindling females were assessed for anxiety-like behaviors in a number of aversive paradigms. Fast rats entered and spent more time in the open arms and spent less time in the closed arms of the elevated plus-maze (EPM) compared to Slow animals. Fast rats had higher conditioned suppression ratios across testing days, defecated less often during conditioning, and successfully disinhibited suppression during extinction in the conditioned emotional response (CER) paradigm compared to Slow-kindlers. In order to pursue these differences in emotional reactivity between the strains and differentiate negative affect from motivational, learning, and impulsive explanations, a separate group of animals were assessed in the light-enhanced acoustic startle chamber, a test of anxiety. When initially exposed to a bright-light, Slow rats significantly increased their startle response while this was not observed in the Fast strain. In combination with previous research on these strains, the present data tentatively suggest that Fast and Slow animals utilize different neural systems in tests of fear and anxiety which may have been co-selected with the direct selection of amygdala-kindling susceptibility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.brainres.2008.08.090DOI Listing
November 2008

Mapping seizure pathways in the temporal lobe.

Epilepsia 2008 ;49 Suppl 3:23-30

Department of Psychology, Institute of Neuroscience, Carleton University, Ottawa, Ontario, Canada.

Interest in temporal lobe seizure pathways has a long history based initially on the human condition of temporal lobe epilepsy (TLE). This interest in TLE has extended more recently into explorations of experimental models. In this review, the network structures in the temporal lobe that are recruited in animal models during various forms of limbic seizures and status epilepticus are described. Common to all of the various models is recruitment of the parahippocampal cortices, including the piriform, perirhinal, and entorhinal areas. This cortical involvement is seen in in vitro and in vivo electrophysiological recordings throughout the network, in trans-synaptic neuroplastic changes in associated network structures manifest at the molecular level, in network energy utilization visualized by 14C2-deoxyglucose uptake, and finally, in the behavioral consequences of network lesions. The conclusions of the animal models reviewed here are very similar to those described for the human condition presented recently in the 2006 Lennox lecture by Warren Blume, and addressed 53 years ago in the quadrennial meeting of the ILAE in 1953 by Henri Gastaut.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1528-1167.2008.01507.xDOI Listing
June 2008

Genetically seizure-prone or seizure-resistant phenotypes and their associated behavioral comorbidities.

Epilepsia 2007 ;48 Suppl 9:30-2

Department of Psychology, Institute of Neuroscience, Carleton University, Ottawa, Ontario, Canada.

It was questioned whether amygdala kindling, a model of temporal lobe epilepsy, is under genetic control, and is associated with comorbid behavioral features. Initially, rats were selectively bred for speed of amygdala kindling, and, in subsequent generations, were assessed in behavioral paradigms to measure activity, emotionality, impulsivity, and learning. Clearly kindling was under genetic control, as two strains were developed to be either Fast or Slow to kindle, and each was associated with different neurological, electrophysiological and behavioral features. Behaviorally, the Fast rats appear much like humans with attention deficit hyperactivity disorder (ADHD), showing easy distraction, hyperactivity and impulsivity, compared to Slow rats.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1528-1167.2007.01398.xDOI Listing
January 2008

Neurodevelopment in seizure-prone and seizure-resistant rat strains: recognizing conflicts in management.

Epilepsia 2007 ;48 Suppl 5:114-8

Neuroscience Institute, Carleton University, Ottawa, Ontario, Canada.

Cytoarchitectural alterations during central nervous system (CNS) development are believed to underlie aberrations in brain morphology that lead to epilepsy. We have recently reported marked reductions in hippocampal and white matter volumes along with relative ventriculomegaly in a rat strain bred to be seizure-prone (FAST) compared to a strain bred to be seizure-resistant (SLOW) (Gilby et al., 2002, American Epilepsy Society 56th Annual Meeting). This study was designed to investigate deviations in gene expression during late-phase embryogenesis within the brains of FAST and SLOW rats. In this way, we hoped to identify molecular mechanisms operating differentially during neurodevelopment that might ultimately create the observed differences in brain morphology and/or seizure susceptibility. Using Superarray technology, we compared the expression level of 112 genes, known to play a role in neurodevelopment, within whole brains of embryonic day 21 (E21) FAST and SLOW rats. Results revealed that while most genes investigated showed near equivalent expression levels, both Apolipoprotein E (APOE) and the beta2 subunit of the voltage-gated sodium channel (SCN2beta) were significantly underexpressed in brains of the seizure-prone embryos. Currently, these transcripts have no known interactions during embryogenesis; however, they have both been independently linked to seizure disposition and/or neurodevelopmental aberrations leading to epilepsy. Thus, alterations in the timing and/or degree of expression for APOE and SCN2beta may be important to developmental cascades that ultimately give rise to the differing brain morphologies, behaviors, and/or seizure vulnerabilities that characterize these strains.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1528-1167.2007.01298.xDOI Listing
November 2007

Ruling out postnatal origins to attention-deficit/hyperactivity disorder (ADHD)-like behaviors in a seizure-prone rat strain.

Behav Neurosci 2007 Apr;121(2):370-9

Institute of Neuroscience, Life Sciences Research Center, Carleton University, Ottawa, ON, Canada.

Adult Fast (seizure-prone) and Slow (seizure-resistant) kindling rat strains exhibit divergent behaviors in paradigms relevant to attention-deficit/hyperactivity disorder (ADHD) in humans. Similar dissociations in rodent behavior have been linked to disparities in early life experience, suggesting that differential maternal care or postnatal interactions may underlie these behaviors. Consequently, the authors compared maternal behavior and preweaning pup weights in these 2 strains under control and cross-fostered conditions and examined its effects on subsequent adult offspring behavior. Ultimately, several distinct maternal behaviors were apparent between the 2 strains under control conditions, and some of those behaviors were then malleable by pup condition. Yet, in spite of the resultant complex maternal patterns across groups, all offspring showed behavioral phenotypes akin to their genetic strain. Thus, a specific postnatal environment is unlikely to underwrite ADHD-like behaviors in the seizure-prone Fast rats, which implicates a genetic or prenatal origin for the ADHD phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1037/0735-7044.121.2.370DOI Listing
April 2007

Effect of focal low-frequency stimulation on amygdala-kindled afterdischarge thresholds and seizure profiles in fast- and slow-kindling rat strains.

Epilepsia 2007 Aug 13;48(8):1604-13. Epub 2007 Apr 13.

Department of Psychology, Institute for Neuroscience, Carleton University, Ottawa, Ontario, Canada.

Purpose: To determine whether low-frequency, 1-Hz sine-wave stimulation (LFS) applied to a fully kindled amygdala focus would show antiepileptic properties in rats that were either naturally seizure prone (Fast) or seizure resistant (Slow).

Methods: Normal twisted and/or "spanning" bipolar electrode configurations were implanted in the amygdalae of adult male Fast and Slow rats. In experiment one, rats were kindled daily to stage-5 levels through one electrode type until stable afterdischarge thresholds (ADTs) were obtained. Next, LFS was applied through the kindled electrode, and ADTs were redetermined 1 min later, and daily for a week, without reapplying the LFS. In experiment two, a single, normal bipolar kindling electrode was implanted in the amygdala and centered between two poles of a spanning electrode. After stable kindled ADTs were obtained, LFS was applied to the amygdala "area" through the spanning electrode. ADTs were redetermined at the kindled electrode as earlier.

Results: LFS through the kindling electrode had no effect on ADTs 1 min later, but the ADTs increased dramatically 24 h later and then slowly returned to baseline over days. In experiment two, LFS applied through the nonkindled spanning electrode also showed a small but significant threshold elevation at the interposing kindled electrode. Importantly, no obvious neuropathology was associated with these LFS treatments.

Conclusions: LFS applied directly to the kindled network has significant threshold-elevating properties that are less evident when applied to the "general area"; here LFS must be delivered through a larger surface area and/or at higher intensity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1528-1167.2007.01077.xDOI Listing
August 2007

Temporal sequence of ictal discharges propagation in the corticolimbic basal ganglia system during amygdala kindled seizures in freely moving rats.

Epilepsy Res 2007 Jan 16;73(1):85-97. Epub 2006 Oct 16.

Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.

We used a multiple channel, single unit recording technique to investigate the neural activity in different corticolimbic and basal ganglia regions in freely moving rats before and during generalized amygdala kindled seizures. Neural activity was recorded simultaneously in the sensorimotor cortex (Ctx), hippocampus, amygdala, substantia nigra pars reticulata (SNr) and the subthalamic nucleus (STN). We observed massive synchronized activity among neurons of different brain regions during seizure episodes. Neurons in the kindled amygdala led other regions in synchronized firing, revealed by time lags of neurons in other regions in crosscorrelogram analysis. While there was no obvious time lag between Ctx and SNr, the STN and hippocampus did lag behind the Ctx and SNr in correlated firing. Activity in the amygdala and SNr contralateral to the kindling stimulation site lagged behind their ipsilateral counterparts. However, no time lag was found between the kindling and contralateral sides of Ctx, hippocampus and STN. Our data confirm that the amygdala is an epileptic focus that emits ictal discharges to other brain regions. The observed temporal pattern indicates that ictal discharges from the amygdala arrive first at Ctx and SNr, and then spread to the hippocampus and STN. The simultaneous activation of both sides of the Ctx suggests that the neocortex participates in kindled seizures as a unisonant entity to provoke the clonic motor seizures. Early activation of the SNr (before the STN and hippocampus) points to an important role of the SNr in amygdala kindled seizures and supports the view that different SNr manipulations may be effective ways to control seizures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.eplepsyres.2006.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1941664PMC
January 2007

Differential noradrenergic influence on seizure expression in genetically Fast and Slow kindling rat strains during massed trial stimulation of the amygdala.

Neuropharmacology 2007 Feb 5;52(2):321-32. Epub 2006 Oct 5.

Institute of Neuroscience, Department of Psychology, Life Sciences Research Building, Carleton University, Ottawa, Ontario K1S 5B6, Canada.

The involvement of alpha(2) noradrenergic receptors during amygdala 'massed' stimulation (MS) was examined in rats that were selectively bred to be seizure-prone (Fast) or seizure-resistant (Slow) to amygdala kindling. The selective alpha(2) noradrenergic agonist guanfacine, or the antagonist idazoxan, was intraperitoneally injected during the MS procedure to study subsequent changes in afterdischarge (AD) threshold, AD duration and behavioral seizure expression. These measurements were again assessed weekly for 2 weeks after the MS treatment. Daily kindling began immediately thereafter. Following 6 stage-5 once daily convulsive seizures, guanfacine or idazoxan were re-administered. With idazoxan, the Slow rats expressed greater numbers of convulsive seizures and longer AD durations compared to guanfacine or saline controls during MS treatment. This pro-convulsive property of idazoxan was absent in Fast rats. By contrast, Fast rats showed enhanced convulsive expression in the presence of guanfacine. In the fully kindled rat, idazoxan and guanfacine differentially impacted seizure duration and severity in the Slow rats, but again not in the Fast rats. These data suggest that some aspect(s) of the alpha(2) noradrenergic system in the Fast and Slow rats are dissimilar and the mechanisms by which these receptors govern seizure genesis and propagation may be genetically controlled and distinct.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuropharm.2006.08.004DOI Listing
February 2007

Play fighting between kindling-prone (FAST) and kindling-resistant (SLOW) rats.

J Comp Psychol 2006 Feb;120(1):19-30

Canadian Centre for Behavioural Neuroscience, Department of Psychology and Neuroscience, University of Lethbridge, Lethbridge, AB, Canada.

Differences in the play behavior of 2 strains of rats suggest that different components of play fighting can be modified independently. The development of play fighting in cross-strain pairs of familiar and unfamiliar rats was examined to determine whether interacting with a non-congruent pair-mate would alter the pattern of play typical for each strain. In both strains, changes in play fighting were observed throughout development, but partner identity appeared to influence play fighting in different ways depending on age. These data suggest that some components of play may be more impervious to changes in social environment than other components.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1037/0735-7036.120.1.19DOI Listing
February 2006

Parahippocampal networks, intractability, and the chronic epilepsy of kindling.

Adv Neurol 2006 ;97:77-83

Department of Psychology, Institute for Neuroscience, Carleton University, Ottawa, Ontario, Canada.

Clearly, the root cause of intractability in epilepsy is currently unknown. Whereas the aforementioned findings may shed light on putative underpinnings, they are by no means an exhaustive list of possibilities. However, new and more effective animal models are continually being created or discovered that take into account genetic predisposition for seizure. At the moment, amygdala kindling appears to be the best choice of the intact animal models. In this vein, the genetically predisposed seizure-prone (Fast kindling) and seizure-resistant (Slow kindling) strains may help speak to many important remaining questions in human epilepsy. Hopefully, these models, to some degree, target correct human subpopulations that are prone or resistant to epilepsy and, when used appropriately, could expedite epilepsy research and future discoveries leading to pharmacoresistance and intractability.
View Article and Find Full Text PDF

Download full-text PDF

Source
February 2006

Differential GABA(A) subunit expression following status epilepticus in seizure-prone and seizure-resistant rats: a putative mechanism for refractory drug response.

Epilepsia 2005 ;46 Suppl 5:3-9

Department of Psychology, Life Sciences Research Center, Carleton University, Ottawa, Ontario, Canada.

Purpose: Two rat strains were selectively bred to be prone (Fast) or resistant (Slow) to amygdala kindling. The first objective of this experiment was to determine whether that selection was specific to kindling or was sensitive more broadly to another seizure induction agent, kainic acid (KA). Second, we investigated whether these strains exhibit distinct molecular responses to KA with respect to GABA(A) receptor subunit expression.

Methods: Development of status epilepticus (SE) was profiled in Fast and Slow rats injected with 20 mg/kg KA (i.p.). Two hours post-SE onset, rats received a sedative dose of sodium pentobarbital. Behavioral profiles included latency to SE, number of wet dog shakes (WDS), and number and duration of stage 3-5 generalized seizures. Rats were killed 24 h post-SE, and alpha(1) and alpha(4) mRNA levels were compared in the hippocampus and amygdala using QPCR.

Results: Slow rats exhibited a much greater latency to SE onset (p < 0.01) and many more WDS (p < 0.01) than Fast rats. During SE, Fast rats spent more time in and exhibited more repeated bouts of generalized stage 3-5 seizures (p < 0.01) than Slow rats. Constitutive levels of alpha1 and alpha4 were not different between the strains in either structure and equivalent reductions in alpha4 were evident 24 h post-SE. However, while Fast rats showed KA-induced reductions in alpha1 in both structures, Slow rats showed significant elevations.

Conclusions: Genetic selection for temporal lobe excitability, manifested as differential amygdala kindling rates, is paralleled by vulnerability to KA-induced SE. Further, these strains exhibited at least one opposing molecular response to SE, namely alpha1 expression. This finding may offer a putative mechanism through which seemingly similar epilepsies can be intractable in some patients but treatable in others.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1528-1167.2005.01001.xDOI Listing
July 2005

Neurosteroids exhibit differential effects on mIPSCs recorded from normal and seizure prone rats.

J Neurophysiol 2005 Sep 31;94(3):2171-81. Epub 2005 May 31.

Neuroscience Research Institute, Department of Psychology, Carleton University, 1125 Colonel By Dr., Ottawa Ontario, K1S 5B6 Canada.

In the perirhinal cortex of seizure prone (SP) rats, GABA(A)-mediated miniature inhibitory postsynaptic currents (mIPSCs) are smaller in amplitude but have longer deactivation phases than mIPSCs recorded in normal control (NC; outbred) rats. These differences in mIPSCs are correlated to the relatively higher alpha1 subunit expression in the NC rat strains and the higher alpha2, alpha3, and alpha5 subunit expression in the SP strain. Using patch-clamp recording, we investigated how the neurosteroids tetrahydrodeoxcorticosterone (THDOC) and allopregnanolone at physiological and pharmacological concentrations may differentially affect the mIPSCs in the perirhinal cortex of brain slices isolated from SP and NC rats. We found that 100 nM THDOC prolonged the time course and increased the amplitude of both the mono- and biphasic mIPSCs in the SP rats, but these effects were smaller in the NC rats. By comparison, allopregnanolone (100 nM) had small effects in both the NC and SP rats. At 1.0 microM, THDOC enhanced mIPSCs in both strains, but this effect was not greater in the SP rat than it was at 100 nM. By contrast, allopregnanolone (500 nM) enhanced the time course of the mIPSCs in both strains but it reduced mIPSC amplitudes as well. THDOC (100 nM) was much more effective than 100 nM allopregnanolone in inducing a tonic current in SP and NC rats. These data show that neurosteroids modulate synaptic activity at synapses having different biophysical behaviors. As differing GABA(A) receptors are targeted by subsets of interneurons, these data suggest these neurosteroids may selectively modulate one inhibitory input over another.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/jn.01233.2004DOI Listing
September 2005

Development of play fighting in kindling-prone (FAST) and kindling-resistant (SLOW) rats: how does the retention of phenotypic juvenility affect the complexity of play?

Dev Psychobiol 2004 Sep;45(2):83-92

Canadian Centre for Behavioural Neuroscience, Department of Psychology and Neuroscience, University of Lethbridge, Lethbridge, Alberta, Canada T1K 3M4.

Rats selectively bred for susceptibility to amygdala kindling (FAST) have been shown to retain neural and behavioral features of the juvenile phase into adulthood. In contrast, rats selectively bred for resistance to amygdala kindling (SLOW) are neurobehaviorally more typically adult. The development of play fighting in male and female rats of both selected lines was studied. Given the apparent association of juvenility and play often noted in the literature for mammals in general, it was predicted that the FAST rats should be more playful and be more likely to retain the juvenile tactics of play that lead to more prolonged and complex patterns of social contact. As expected, FAST rats initiated more playful attacks and were more likely to defend against attacks than SLOW rats as both juveniles and adults. Unexpectedly, however, both selected lines exhibited patterns of defense that reduced the likelihood of complex and prolonged social contact. Importantly, the two selected lines did so by very different means. The FAST rats did so by avoiding contact whereas the SLOW rats did so by responding in an adult-typical manner that blocks contact. That is, the FAST rats exaggerated the changes typically occurring at puberty whereas the SLOW rats, at all ages, responded in a more adult manner. These data suggest that the different components of play fighting do not change uniformly with changes in the neurobehavioral underpinnings of juvenility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/dev.20016DOI Listing
September 2004

Amygdala amino acid and monoamine levels in genetically Fast and Slow kindling rat strains during massed amygdala kindling: a microdialysis study.

Eur J Neurosci 2004 Jul;20(1):185-94

Department of Psychology, Life Sciences Research Building, Carleton University, Ottawa, Ontario, K1S 5B6, Canada.

We investigated the neurochemistry of epileptic seizures in rats selectively bred to be seizure-prone (Fast) vs. seizure-resistant (Slow) to amygdala kindling. Microdialysis was used to measure levels of amino acids [glutamate, aspartate and gamma-aminobutyric acid (GABA)] and monoamines (noradrenaline, dopamine and serotonin) during 'massed' stimulation (MS) (every 6 min) of the ipsilateral amygdala for a total of 40 stimulation trials. Behavioral seizure profiles together with their afterdischarge thresholds (ADTs) and associated durations were assessed during the procedure, and subsequently were redetermined 1, 7 and 14 days later. Then normal 'daily' kindling commenced and continued until the animal reached the fully kindled state. During MS, several generalized seizures were triggered in Fast rats that were associated with long afterdischarge (AD) durations and intermittent periods of elevated thresholds, but in Slow rats, most stimulations were associated with stable ADTs and short ADs. Progressively increasing extracellular glutamate and decreasing GABA was observed in Fast rats during the MS, whereas Slow rats showed levels similar to baseline values. Levels of noradrenaline and dopamine, but not of serotonin, were also increased in both strains throughout the MS treatment. In Fast rats, a dramatic lengthening of AD durations occurred 7 and 14 days following MS, as well as subsequent strong positive transfer to daily kindling, all of which were not seen in Slow rats. Together, these results show that repeated, closely spaced stimulations of the amygdala can differentially alter excitatory and/or inhibitory transmitter levels in a seizure network, and that sensitivity to this manipulation is genetically determined.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1460-9568.2004.03477.xDOI Listing
July 2004

Activin mRNA induced during amygdala kindling shows a spatiotemporal progression that tracks the spread of seizures.

J Comp Neurol 2004 Aug;476(1):91-102

Section on Functional Neuroanatomy, National Institute of Mental Health, National Institutes of Health, United States Department of Health and Human Services, Bethesda, Maryland 20892-4070, USA.

The progressive development of seizures in rats by amygdala kindling, which models temporal lobe epilepsy, allows the study of molecular regulators of enduring synaptic changes. Neurotrophins play important roles in synaptic plasticity and neuroprotection. Activin, a member of the transforming growth factor-beta superfamily of growth and differentiation factors, has recently been added to the list of candidate synaptic regulators. We mapped the induction of activin betaA mRNA in amygdala and cortex at several stages of seizure development. Strong induction, measured 2 hours after the first stage 2 (partial) seizure, appeared in neurons of the ipsilateral amygdala (confined to the lateral, basal, and posterior cortical nuclei) and insular, piriform, orbital, and infralimbic cortices. Activin betaA mRNA induction, after the first stage 5 (generalized) seizure, had spread to the contralateral amygdala (same nuclear distribution) and cortex, and the induced labeling covered much of the convexity of neocortex as well as piriform, perirhinal, and entorhinal cortices in a nearly bilaterally symmetrical pattern. This pattern had filled in by the sixth stage 5 seizure. Induced labeling in cortical neurons was confined mainly to layer II. A similar temporal and spatial pattern of increased mRNA expression of brain-derived neurotrophic factor (BDNF) was found in the amygdala and cortex. Activin betaA and BDNF expression patterns were similar at 1, 2, and 6 hours after the last seizure, subsiding at 24 hours; in contrast, c-fos mRNA induction appeared only at 1 hour throughout cortex and then subsided. In double-label studies, activin betaA mRNA-positive neurons were also BDNF mRNA positive, and they did not colocalize with GAD67 mRNA (a marker of gamma-aminobutyric acidergic neurons). The data suggest that activin and BDNF transcriptional activities accurately mark excitatory neurons participating in seizure-induced synaptic alterations and may contribute to the enduring changes that underlie the kindled state.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cne.20197DOI Listing
August 2004

Differential neuroplastic changes in neocortical movement representations and dendritic morphology in epilepsy-prone and epilepsy-resistant rat strains following high-frequency stimulation.

Eur J Neurosci 2004 Apr;19(8):2319-28

Behavioural Neuroscience Research Group, Department of Psychology, University of Calgary, Calgary, Alberta, Canada T2N 1 N4.

The epileptogenic-prone (FAST) and epileptogenic-resistant (SLOW) rat strains have become a valuable tool for investigating the neurochemical and neurophysiological basis of epilepsy. This study examined the two strains with respect to their neocortical movement representations and cortical layer III pyramidal cell dendritic morphology in both control and potentiated conditions. FAST and SLOW rats received high-frequency stimulation of the corpus callosum in order to induce long-term polysynaptic potentiation of the transcallosal pathway to the sensorimotor neocortex. Baseline-evoked potentials of this pathway were recorded in the left hemisphere before stimulation, and following 5, 10, 15 and 20 days of high-frequency stimulation. All rats then underwent high-resolution intracortical microstimulation (ICMS) in order to assess functional movement representations of the left caudal forelimb area of the sensorimotor cortex. Immediately following ICMS, the brains were stained with the Golgi-Cox method, and the length, branching and spine density of frontal and occipital neocortical layer III pyramidal neurons were measured. We observed that high-frequency stimulation induced similar increases in polysynaptic potentiation in both rat strains; however, only the FAST strain showed an increase (doubling) in the size of their motor maps. We also observed decreases in dendritic length and branching in the FAST rats, and the opposite profile in the SLOW rats. The potentiated FAST rats also showed an increase in spine density. Our results suggest that differences in susceptibility to epileptogenesis may result in a differential response to stimulation-induced plasticity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.0953-816X.2004.03332.xDOI Listing
April 2004

Anxiety in rats selectively bred for Fast and Slow kindling rates: situation-specific outcomes.

Stress 2003 Dec;6(4):289-95

Institute of Neuroscience, Carleton University, Ottawa, Ont, Canada.

Rats selectively bred for amygdala excitability, realized by fast or slow kindling epileptogenesis, were previously reported to exhibit differential levels of anxiety. Although the Slow kindling rats generally appeared more anxious in several behavioral tests, under certain test conditions the Fast kindling rats displayed greater anxiety or stressor reactivity. The present investigation confirmed that in a test of anxiety comprising suppression of consumption of a palatable snack in an unfamiliar environment, the Slow kindling rats exhibited greater anxiety and that this effect was attenuated by diazepam. Likewise, the acoustic startle response was greater in the Slow kindling rats. However, the fear-potentiated startle response was more pronounced in Fast kindling rats, particularly among females, irrespective of whether the test parameters elicited moderate or high startle amplitudes. The elevated startle in the Slow rats, and the fear potentiated startle in the Fast rats, were attenuated by diazepam. These data indicate the need to differentiate subtypes of anxiety in animal models, and raise the issue that anxiety elicited by specific environmental triggers may interact with genetically determined trait characteristics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10253890310001638136DOI Listing
December 2003

Differential sensitivity of genetically Fast vs. Slow kindling rats strains to GABAergic convulsive agents.

Neuropharmacology 2003 Dec;45(7):918-24

Psychology Department, McMaster University, Hamilton, Ontario, Canada L8S 4K1.

Following selective breeding for seizure-proneness vs. seizure-resistance to amygdala kindling, two strains of rats were developed with non-overlapping kindling rates, i.e. the number of stimulations required to develop fully generalized convulsive seizures (Epilepsy Res. 35 (1999) 183). In the temporal cortices of these two strains, the local seizure thresholds to electrical stimulation have been reported to be approximately two times lower in the seizure-prone (Fast kindling) compared to the seizure-resistant (Slow kindling) strain (McIntyre et al., 1999). In the present experiment, the pharmacological sensitivities of the two strains to three GABAergic antagonists, pentylenetetrazol, bicuculline and picrotoxin, were determined, and compared to the glycine antagonist, strychnine. Paralleling kindling epileptogenesis, naïve rats of the Fast kindling strain developed convulsive seizures to doses of the GABAergic antagonists that were significantly (approximately 30%) lower than the naïve Slow kindling strain. In contrast, there were no strain differences in their response to strychnine. These data indicate substantial GABAergic sensitivity differences between the two strains with an emphasis on forebrain mechanisms, which is consistent with other physiological and molecular data related to their differential profiles of epileptogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/s0028-3908(03)00252-1DOI Listing
December 2003

Secondary generalization of hippocampal kindled seizures in rats: examining the role of the piriform cortex.

Brain Res 2002 Dec;957(1):152-61

Department of Psychology, Life Sciences Research Center, Carleton University, Ontario Ottawa K1S 5B6, Canada.

A primary feature of epilepsy is the potential for focal seizures to recruit distant structures and generalize into convulsions. Key to understanding generalization is to identify critical structures facilitating the transition from focal to generalized seizures. In kindling, development of a primary site leads progressively to secondarily generalized convulsions. In addition, subsequent kindling of a secondary site results in rapid kindling from that site, presumably because of its facilitated access to the primary kindled network. Here, we investigated the role of the piriform cortex in convulsive generalization from a secondary site kindled in the hippocampus after primary site amygdala kindling. In a necessarily complicated design, rats initially experienced forebrain commissurotomy to lateralize the experiment to one hemisphere. Then the amygdala was kindled and, 3 weeks later, it was electrically-triggered into status epilepticus, which destroyed the ipsilateral piriform cortex. This experience occurred several days before secondary site kindling of the dorsal hippocampus. In rats with complete piriform cortex loss, there was no disruption in kindling or convulsive seizure expression from the hippocampus. However, when damage also involved parts of the perirhinal, insular and entorhinal cortices, convulsive expression was blocked. Although other evidence suggests that piriform lesions affect generalization of primary site kindling, the present study shows that they do not alter secondary site kindling in the dorsal hippocampus. The additional involvement of parahippocampal cortical areas in convulsive expression suggests an important functional association between these cortical regions and the hippocampus in seizure propagation and clinical expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/s0006-8993(02)03617-xDOI Listing
December 2002

Divergent GABA(A) receptor-mediated synaptic transmission in genetically seizure-prone and seizure-resistant rats.

J Neurosci 2002 Nov;22(22):9922-31

Neuroscience Research Institute, Carleton University, Ottawa, Ontario, Canada K1S 5B6.

Recent evidence suggests that abnormal expression of GABA(A) receptors may underlie epileptogenesis. We observed previously that rats selectively bred to be seizure-prone naturally overexpressed, as adults, GABA alpha subunits (alpha2, alpha3, and alpha5) seen at birth, whereas those selected to be seizure-resistant overexpressed the adult, alpha1 subunit. In this experiment, we gathered GABA miniature IPSCs (mIPSCs) from these strains and correlated their attributes with the subunit expression profile of each strain compared with a normal control strain. The mIPSCs were collected from both cortical pyramidal and nonpyramidal neurons. In seizure-prone rats, mIPSCs were smaller and decayed more slowly than in normal rats, which in turn were smaller and slower than in seizure-resistant rats. A detailed analysis of individual mIPSCs revealed two kinds of postsynaptic responses (those with monoexponential vs biexponential decay) that were differentially altered in the three strains. The properties of monoexponentially decaying mIPSCs did not differ between pyramidal and nonpyramidal neurons within a strain but differed between strains. In contrast, an interaction was observed between cell morphology and strain for biexponentially decaying mIPSCs. Here, the mIPSCs of pyramidal neurons in the seizure-resistant rats formed a distinct subpopulation compared with the seizure-prone rats; yet in the latter rats, it was the mIPSCs of the nonpyramidal neurons that were unique. Given these differences, we were surprised to find that the total inhibitory charge transfer between the strains was similar. This suggests that the timing of inhibition, particularly slow inhibitory neurotransmission between nonpyramidal neurons, may be a contributing factor in seizure genesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6757834PMC
November 2002

Conceptual, spatial, and cue learning in the Morris water maze in fast or slow kindling rats: attention deficit comorbidity.

J Neurosci 2002 Sep;22(17):7809-17

Institute of Neuroscience, Carleton University, Ottawa, Ontario, Canada, K1S 5B6.

Rat lines selectively bred for differences in amygdala excitability, manifested by "fast" or "slow" kindling epileptogenesis, display several comorbid features related to anxiety and learning. To assess the nature of the learning deficits in fast kindling rats, performance was evaluated in several variants of a Morris water-maze test. Regardless of whether the location of the platform was fixed or varied over days (matching-to-place task), the fast rats displayed inferior performance, suggesting both working and reference memory impairments. Furthermore, when the position of the platform was altered after the response was acquired, fast rats were more persistent in emitting the previously acquired response. The poor performance of fast rats was also evident in both cued and uncued tasks, indicating that their disturbed learning was not simply a reflection of a spatial deficit. Moreover, fast rats could be easily distracted by irrelevant cues, suggesting that these animals suffered from an attentional disturbance. Interestingly, when rats received several training trials with the platform elevated, permitting them to develop the concept of facile escape, the performance of fast rats improved greatly. The performance disturbance in fast rats may reflect difficulties in forming a conceptual framework under conditions involving some degree of ambiguity, as well as greater distractibility by irrelevant cues. These various attributes of the fast rats may serve as a potentially useful animal model of disorders characterized by an attention deficit.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6757963PMC
September 2002

Kindling: some old and some new.

Epilepsy Res 2002 Jun;50(1-2):79-92

Department of Psychology, Institute for Neuroscience, Life Science Research Building, Carleton University, Ottawa, Ont., Canada.

A brief review of kindling is provided, which highlights some important points of historical interest often overlooked by researchers. These points include the fact that the original rating scale of convulsive seizures presented by Racine 'EEG Clin. Neurophysiol 32 (1972) 281'. was based on amygdala kindling, and may not be applicable to kindling from other sites. The functional anatomy of these convulsive seizures was similarly addressed. Also emphasized was the observation that kindling results ultimately in spontaneous seizures, seemingly identical to those seen in models of status epilepticus (SE), and can provide a unique perspective on those seizures because of its controlled natural history and minimal brain damage. Much of the recent work described here focused on genetic susceptibility versus resistance to kindling, as witnessed by the Fast and Slow kindling rat strains. The results of those studies indicated substantial strain differences in GABAergic function in different limbic structures associated with GABA(A) subunit expression, spontaneous miniature inhibitory postsynaptic currents (mIPCs) and behavioral comorbidities. We concluded the review with our recent attempt to discover consistent and unique gene profile differences associated with the different seizure predispositions of the Fast and Slow kindling rat strains.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/s0920-1211(02)00071-2DOI Listing
June 2002

Changes in extracellular levels of amygdala amino acids in genetically fast and slow kindling rat strains.

Brain Res 2002 Aug;946(1):31-42

Institute of Neuroscience, Department of Psychology, Life Sciences Research Building, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario K1S 5B6, Canada.

A neurochemical basis for many of the epilepsies has long been suspected to result from an imbalance between excitatory and inhibitory neurotransmitter mechanisms. Data supporting changes in extrasynaptic amino acid levels during epileptogenesis, however, remain controversial. In the present study, we used in vivo microdialysis to measure the levels of extracellular GABA (gamma-aminobutyric acid) and glutamate during seizure development in rats with a genetic predisposition for (Fast), or against (Slow), amygdala kindling. Dialysates were collected from both amygdalae before, during, and up to 12 min after a threshold-triggered amygdala afterdischarge (AD). One hour later, samples were again collected from both amygdalae in response to a hippocampal threshold AD. Daily amygdala kindling commenced the next day but without dialysis. After the rats were fully kindled, the same protocol was again employed. Amino acid levels were not consistently increased above baseline with triggered seizures in either strain. Instead, before kindling, a focal seizure in the Slow rats was associated with a large decrease in GABA in the non-stimulated amygdala, while amino acid levels in the Fast rats remained near baseline in both amygdalae. Similar results were seen after kindling. By contrast, before and after kindling, hippocampal stimulation caused large decreases in all amino acid levels in both amygdalae in both strains. These data suggest that, in response to direct stimulation, extracellular amino acid concentrations remain stable in tissues associated with either greater natural (Fast) or induced (kindled Fast/Slow) excitability, but are lowered with indirect stimulation (hippocampus) and/or low excitability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/s0006-8993(02)02821-4DOI Listing
August 2002

Animal models of limbic epilepsies: what can they tell us?

Brain Pathol 2002 Apr;12(2):240-56

Department of Neuroscience, University of Pennsylvania School of Medicine, Children's Hospital of Philadelphia, 19104-4318, USA.

In this review, we have provided an overview of the implementation and characteristics of some of the most prevalent models of temporal lobe epilepsy in use in laboratories around the world today. These include spontaneously seizing models with status epilepticus as the initial precipitating injury (including the kainate, pilocarpine, and electrical stimulation models), kindling, and models of drug refractoriness. These models share various features with one another, and also differ in many aspects, providing a broader representation of the full spectrum of clinical limbic epilepsies. We have also provided a brief introduction into how animal models of temporal lobe epilepsy facilitate use of modern state-of-the-art techniques in neurobiology to address critical questions in the pathogenesis of epilepsy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2441870PMC
http://dx.doi.org/10.1111/j.1750-3639.2002.tb00439.xDOI Listing
April 2002
-->