The relationship between audiogenic seizure (AGS) susceptibility and forebrain tone-responsiveness...

Physiology & Behavior 70 (2000) 297–309

0031-9384/00/$ – see front matter © 2000 Elsevier Science Inc. All rights reserved.PII: S0031-9384(00)00260-2

The relationship between audiogenic seizure (AGS) susceptibility and forebrain tone-responsiveness in genetically AGS-prone Wistar rats

Antti Valjakka*, Marjut Jaakkola

a

, Jukka Vartiainen

b

, Hannu Olkkonen

c

, Antonina Semiokhina

d

, Irina Fedotova

d

, Jussi Virkkala

e

, Jukka Ylikoski

e

, Leena Tuomisto

a

a

Department of Pharmacology and Toxicology, University of Kuopio, P.O.B. 1627, SF-70210 Kuopio, Finland

b

NOKIA Research Center, Tampere, Finland

c

Department of Applied Physics, University of Kuopio, Kuopio, Finland

d

Moscow State University, Moscow, Russia

e

Department of Otholaryngology, University Central Hospital of Kuopio, Kuopio, Finland

Received 22 November 1999; received in revised form 13 March 2000; accepted 14 March 2000

Abstract

The present study characterized the intensity–response functions of extracellular field responsiveness of different cortical/subcorticalstructures of the forebrain following the free-field presentation of tone stimuli, within a population of genetically audiogenic seizure(AGS)-prone KM-Wistar rats. The neural response properties of each case were compared to its propensity to exhibit AGSs during thecontinuous tone stimulation (15 kHz, 90 s at max.). The amplitudes or slope components of the evoked responses and their peak latenciesshowed significant positive (amplitude and slope) and negative (peak latency) Bolzmann’s sigmoid relationships with the onset-latency ofAGS. These relationships, with areal differences in the slopes of saturation functions, applied for the three different data sets recorded si-multaneously from the stratum radiatum dendritic layer of the hippocampal CA1 area, primary auditory cortex layers II–IV, and frontalcortex surface. In addition, the similar type of functions between the evoked response variables and AGS onset latency held when all theareas were considered together. These data suggest that the neural responsiveness to acoustic stimulation of the primary sensory, multi-modal and association cortices of the forebrain may altogether contribute to the seizure initiation by that modality in the geneticallyAGS-prone rats. It has been previously shown that there exist abundant and dispersed auditory projections from these forebrain areas tothe brain stem and spinal cord, structures that are generally considered to be the key predisposing factors in the generation of AGS.Hence, the types of correlation found reflect the subject-specific stage of forebrain responsiveness, being either related or unrelated to geneticAGS-specific changes, and possibly its triggering impact upon the lower brain AGS network. Accordingly, the mere comparison of fore-brain response measures of these AGS-prone animals with those of the AGS-resistant ones could not reveal the result presented.© 2000 Elsevier Science Inc. All rights reserved.

Keywords:

Evoked field potentials; Acoustic stimuli; Forebrain; Rat; Audiogenic seizure; Epilepsy

1. Introduction

In previous studies, two issues have been considered us-ing strains of genetically epilepsy-prone rats, which are sus-ceptible to sound-induced seizures: 1) those brain areas thatare involved in the generation of different stages of audio-genic seizure (AGS), and 2) those cellular, biochemical, andphysiological abnormalities specific to the different brainareas of AGS-prone animals.

With regard to the first issue, the neurochemical manipu-lations of excitatory/inhibitory amino acid transmission ofthe inferior colliculus (IC) [1–13] and the lesioning [14] andtransection [15] studies of different brain structures, which

are anatomically related to the IC, have led to the proposalthat the IC plays a key role in transforming excitation ofacoustic stimulation into the neural overexcitation of AGSthat finally spreads to the multiple of brain areas [1,2,14,15–21]. The IC and superior colliculus (SC) of the midbrain andtheir projections, via the reticularis pontis oralis nucleus ofthe hindbrain to the spinal cord, have been suggested to beresponsible for the initiation and progression phases ofAGSs, respectively [13–16,22,23].

With regard to the second issue, the reported AGS strain-specific changes in the IC involve increased levels ofglutamate [24] and aspartate [25], reduced concentration/in-nervation density of both norepinephrine [26–28] and sero-tonin [29–31], decreased levels of GABA [25,32], and hy-posensitivity to GABA [5,32]. However, both in the IC and

* Corresponding author. Tel.: 358-17-162435; Fax: 358-17-162424

E-mail address:

[email protected]

298

A. Valjakka et al. / Physiology & Behavior 70 (2000) 297–309

SC a rise in the number of GABA-positive neurons [33,34]and also increased levels of GABA [24,35] have been re-ported. In line with these latter changes, the central nucleusof the IC and deep layers of the SC show reduced excitabil-ity to sound stimulation [22,36] when compared to AGS-re-sistant control animals.

Many types of AGS susceptibility related alterations inthe discrete forebrain areas have also been documented,which may make the respective brain areas more responsiveto excitation by sound. These alterations in the hippocam-pus of Sprague–Dawley rats include an increase in potas-sium-stimulated [

3

H]-aspartate release [37], enhancement ofpaired-pulse facilitation of CA1 pyramidal cells by acousticstimulation [38], and reduced synaptic inhibition of the CA1area as shown in vitro [39–41] and in vivo [38]. In thatstructure, increased levels of both glutamate and aspartate[42], a reduction in concentrations of GABA [42], and sero-tonin [29], a decrease in 5-HT

1A

binding [30], and seroto-nin/noradrenergic innervation density [26,28,31], increasedbinding of naloxone-sensitive dihydromorphine [43], andreduced levels of histamine [44,45] have also been reported.In the cerebral cortex and thalamus, on the other hand, re-ductions in the levels of serotonin [29,31,46], norepineph-rine [46], histamine [44,45], GABA [25], and neuronalGABA transporter [47], but increases in glutamate [24,25]and aspartate [25] have been found. A possible functionalconsequence of these multiple of changes may be that theamygdala [48] and hippocampal [49,50] kindling of theforebrain are accelerated in the AGS-prone rats.

Consequently, based on these number of results, wherethe forebrain properties of AGS-prone and -resistant strainswere compared, some influences of the structures above themid-/hindbrain in the generation of AGSs have been consid-ered possible.

The difficulty in comparing the cellular and biochemicaldifferences between the seizure-prone and -resistant strains,however, may be the fact that the observed strain differ-ences could be related to some unknown factors other thanthe AGS susceptibility. In any case, the forebrain structurescan be surmised to be involved in this seizure model be-cause 1) the limbic and neocortical areas of the forebrainprovide intense and dispersed feedback projections into thespinal cord motor neurons, either directly or through differ-ent synaptic steps in the brain stem [51]; and, conversely, 2)the brain stem AGS network has a functional impact on theforebrain structures [52–57]. Based on these arguments themodulatory influences of variations in the states of differentforebrain areas should first be evaluated within a populationof AGS-prone animals.

The present study characterized the neural population re-sponsiveness of different forebrain structures to the free-field presentation of tone pulses in freely behaving, geneti-cally AGS-prone KM-Wistar rats. The field potential re-sponses recorded from the stratum radiatum dendritic layerof the hippocampal CA1 area, primary auditory cortex lay-ers II–IV, and frontal cortex surface were consequently

compared with the subjects’ AGS susceptibility, determinedas the latency needed for the induction of AGSs during thecontinuous-tone presentation.

2. Materials and methods

2.1. Animals

Genetically epilepsy-prone rats of the KM (Krushinsky–Molodkina) strain, bred at the Moscow State University,were used as experimental subjects in the present study. TheKM-rats are genetically inclined to epileptic seizures whenstimulated by sound [58]. At the age of 5 months, the ani-mals were transported to Kuopio University and thereafter,individually housed in cages with free access to food (Lac-tamin R36, Lactamin Ab, Sweden) and tap water, and keptin a room controlled for temperature (22

6

1

8

C) and light(0700–1900 h). The animals were allowed to habituate tothese conditions for a month before the experiments werestarted. All procedures with the animals were reviewed bythe Animal Use and Care Committee of the University ofKuopio and approved by the Kuopio provincial govern-ment, and the protocols adhered to the recommendations ofthe declaration of Helsinki.

2.2. Surgery

The rats were anesthetized with intraperitoneal injectionsof chloral hydrate (350 mg/kg) and placed into a DavidKopf

®

stereotaxic frame with the lambda and bregma in thesame horizontal plane. The coordinates were calculatedfrom the Bregma according to the rat brain atlas [59]. Thehippocampal deep electrode (a single-strand stainless steelwire, diameter 125

m

m, Teflon-coated except at the tip) waspositioned on the right hippocampus at the coordinates ofAP

2

4.1, L 2.6, and DV

2

2.8, within the stratum radiatumdendritic layer of the CA1 area. A similar electrode was po-sitioned within the pyramidal cell layers II–IV of the rightprimary auditory cortex at the coordinates of AP

2

5.3, L3.0, and DV

2

5.0, using a medial–lateral positioning angleof 38.5

8

. A miniature stainless steel watch screw, driveninto the frontal bone above the right frontal cortex, at the co-ordinates of AP 1.5 and L 2.0, served as a cortical recordingelectrode. The reference and indifferent screw electrodeswere driven bilaterally into the occipital bone. An additionalanchoring screw was placed in the left frontal bone. Thewhole assembly of electrodes, which were attached withwires to pins in the socket, was anchored on the skull withdental acrylic repair material. These operations were per-formed on 14 KM rats. A recovery period of at least 1 weekelapsed before the experimentation was started.

2.3. Behavioral testing for AGS susceptibility

For the AGS susceptibility testing, after the electrode place-ments, the rat was placed in a spherical Plexiglas chamber andstimulated with continuous tone (90 dB, 15 kHz) for a maxi-


299

mum duration of 90 s if no behavioural changes appeared oruntil the rat reached a running episode, which corresponded tothe score of 1 on the scale of Jobe et al. [60]; see also [58] and[61] for the present method). Of the eight rats that were ac-cepted for the detailed electrophysiological testing (see the cri-teria below), two rats did not show any behavioral changesduring the whole 90-s stimulation period of AGS testing, andhad scores of 0. Those cases were assigned the maximum AGSonset latencies of 90 s. All the other six rats, within 1–40 s, ei-ther reached the generalized seizure at once or the running epi-sode, which invariably led to the generalized AGS within a fewseconds. In these rats, the AGS onset latency was measured asthe time that elapsed from the beginning of sound presentationto the emergence of the running stage/generalized seizure.

2.4. Evoked potential recordings

2.4.1. Recording criteria

The electrophysiological recordings, conducted in a Fara-day cage, were started 4 weeks after the AGS susceptibilitytesting. For the tone stimulations, the rat was placed within asquare, top-open Plexiglas chamber (floor area 30

3

30 cm,covered with sawdust) in which two loud-speakers weremounted on opposite walls. The recordings were acquiredfrom the freely behaving rats when they were standing, sit-ting, or lying still but were alert and immobile. The samplingrate of 5 kHz per channel was applied. The 1.5-ms tonepulses were delivered during the first quarter of the 1-s re-cording period and the associated trigger pulse was used as amark for averaging the repeated measurements, off-line. Theresponses to each tone presentation were recorded simulta-neously from the frontal cortex, primary auditory cortex, andhippocampus, and stored on the PC’s hard disk. The 1.5-mstone pulse, 8 kHz in frequency, was generated with the useof a separate microcomputer and a programmable soundcard. Tones were delivered at 10 to 20-s intervals.

During the preliminary stimulation sessions, 8 out of the14 surgically operated rats showed acceptable responsewaveforms in all the three brain regions described above (ex-cept for one case of the primary auditory cortex, which hadto be discarded due to the contact artefact;

n

5

7 for thatbrain area). These eight rats were included in the detailedevoked potential recordings and analyses described below.The criteria for the response acceptance from the differentbrain areas were the following. The present response wave-forms acquired from the dendritic stratum radiatum layer ofthe hippocampal CA1 area (see Fig. 1) corresponded in theirforms to those of the click-evoked responses determined ear-lier for that area by depth-profile recordings in the rat [62].Similarly, the present tone-evoked response waveform fromthe pyramidal cell layer II–IV of the primary auditory cortex(see Fig. 1) corresponded in its form and latency to the P1acomponent, which is characteristic of the primary cortexarea [63–67] and its supragranular cell layer II–IV as shownin rats [63]. The frontal cortex responses (see Fig. 1) wereconsistent with those reported in guinea pigs [68].

2.4.2. Recordings

(a) Assessment of forebrain tone responsiveness: fifteenfield-potential responses generated by each of the three stimu-lation intensities (92, 98, and 105 dB) were acquired from eachrat during the first baseline recording. A few days later, duringthe second baseline recording, this was repeated, but using awider range of stimulation intensities: 79, 92, and 105 dB. (b)Testing of the effects of a single AGS on forebrain tone respon-

Fig. 1. (A) The single-sweep samples of extracellular field potentials and theappearance of tone-evoked responses in the primary auditory cortex layers II-IV (A), stratum radiatum layer of the hippocampal CA1 area (H) and frontalcortex surface (F). Synchronous recordings from A, H, and F. The sequence ofA, H, and F descriptions also applies in parts B–D. (B) Marking methods usedin computing the amplitude (y-axis difference between point 2 and the lineconnecting points 1 and 3), slope (angle between points 1 and 2), and latency(x-axis difference between point 2 and the moment of tone pulse delivery) ofevoked potentials in different forebrain structures. (C) The grand group aver-ages of records for each brain structure with increasing sound intensity. (n 5 7rats for A and n 5 8 rats for H and F, in this and subsequent figures.) Note thatthe depolarization potential first appears in the primary auditory cortex, then inthe hippocampus, and soon after that in the frontal cortex. Compared to A or H,the depolarization potential is reversed in F due to the surface recording. (D)The same as in C but the group of eight rats was randomly divided into twosubgroups which were either control-handled (n 5 4) or subjected to a genral-ized AGS (n 5 4) between the two recording sessions. Note the close corre-spondence of averaged responses between the two groups during the baselinecondition and the lack of effects of the subsequent control handling or AGS.

300


siveness: the effects of a single sound-induced AGS and con-trol handling on the tone responsiveness of the different fore-brain structures were additionally investigated. The day afterthe second baseline recording, the rats were divided into twogroups: those that were subjected to the sound-induced AGSwithin a spherical chamber, and those that were briefly placedin the same chamber but were not stimulated. In the formergroup, three rats reached the generalized seizure stage (score 9)during the first 90-s stimulus period, but one case did not sufferseizure, although 3

3

90-s stimulus periods were tested. Ninedays later, this rat was, however, successfully stimulated, dur-ing the first 90-s stimulation period, to have a generalizedAGS. Both groups of rats were tested, 15 min after the AGS in-duction/control handling, for the evoked potentials using,again, the stimulation intensities of 79, 92, and 105 dB.

2.5. Analyses

2.5.1. Computation methods of electrophysiological data

In each rat, the analysis comprised the averaging of therepeated measurements, after which the peak latencies, am-plitudes, and slopes of the averaged field-potential re-sponses from each brain region were computed (see Fig. 1Bfor the method). In addition, the distribution of power den-sity over the time–frequency domain for each single sweepof recording was computed first, and then from the resultingindividual maps, the respective group averages were ob-tained. These maps were computed from the signal data dig-itally high-pass filtered at the 30 Hz level. This lattermethod is able to reveal the whole duration of gamma fre-quency (the considered range: 30–200 Hz) activation in re-lation to the sensory stimulation, also during the later stagesof responses, which show marked latency jitter among theoscillation cycles and that thereby will be cancelled out inthe waveform averaging method.

2.5.2. Comparisons between forebrain tone responsivenessand AGS susceptibility

The data from the first and second baseline recordingswere combined to represent, as a single normalized vari-able, the tone responsiveness of each of the three forebrainstructures, and these variables were plotted against the AGSonset latency of each subject.

2.5.3. Determination of the effects of a single AGS on fore-brain tone responsiveness

The effects of the control handling and a single AGS on theneural tone responsiveness, within the three different forebrainstructures, were determined using the data from the secondbaseline recording and from the recording acquired after that.

2.5.4. Statistics

The goodness of fit of the linear regressions and Bolz-mann’s nonlinear sigmoid regressions, between the evokedresponse and the seizure onset latency, were expressed as the

r

2

-values. The statistical significances of the linear correla-tions were additionally evaluated with the use of the Pearsonlinear correlation test. The effects of group, time, and time

3

group interactions of the evoked response data were ob-tained from the analysis of variance for the repeated mea-surements. The nonparametric group effects were furthertested. The estimation of variations of the group means fromthe true population means are expressed as the standard er-ror of the means (SE).

3. Results

3.1. Assessment of the profiles of forebrain tone responsivess during baseline conditions

3.1.1. Response waveforms

Figure 1A shows the examples of field potential record-ings and tone pulse-evoked responses acquired simulta-neously from the primary auditory cortex, hippocampus,and frontal cortex, in a single case.

The random background EEG activity canceled out in thegrand group averages of single records and disclosed the recur-ring stereotyped phases of evoked potentials whose waveformpatterns were specific for each brain region (Fig. 1B–D). Fig-ure 1C shows the whole group averages of eight rats during thefirst baseline recording, and Fig. 1D (left side) the averages ofthe two different subgroups (

n

5

4 rats for each) during thesecond baseline recording of evoked responses in the three dif-ferent brain structures as the function of stimulus intensity. Theaveraged waveforms established that the recordings were re-peatable in the sense that 1) the averaged responses of the twosubgroups were close to each other as shown in the left part ofFig. 1D, and 2) the compatible effects of variations in thesound intensity became evident both in part C and D, whichrepresented the different recording sessions.

3.1.2. Response sizes

The peak latencies, slopes, and amplitudes of the evokedresponses were computed for each case by applying themethods illustrated in Fig. 1B (see the figure text). In all thebrain regions studied, both the amplitude and slope of theevoked potentials were significantly increased when thetone intensity was increased either from 92 to 105 dB (

p

-values

,

0.05, Fig. 2A; corresponds to waveform datashown in Fig. 1C) or from 79 to 105 dB (

p

-values

,

0.003,Fig. 2B; corresponds to waveform data shown in Fig. 1D).The response latencies were, however, not significantlychanged by these stimulus intensity increments. The slightdecrements in the response latencies, from 92 to 105 dB,were 0.9

6

0.4 ms in the primary auditory cortex, 1.3

6

0.8ms in the hippocampus, and 1.4

6

0.9 in the frontal cortex(Fig. 2A). The whole group means of tone-evoked responselatencies were 13.5

6

0.4 ms in the primary auditory cortex,24.2

6

0.6 ms in the hippocampus, and 25.3

6

0.7 ms in thefrontal cortex, when the whole 92–105 dB range of stimula-tion intensities was considered. The response latency differ-ence between the frontal cortex and auditory cortex was12.2

6

0.8 ms (

p

,

0.001), 10.9

6

0.7 ms between the hip-pocampus and auditory cortex (

p

,

0.001), and 1.2

6

0.4ms between the frontal cortex and hippocampus (

p

.

0.05).


301

These quantitative results, in concordance with Fig. 1A, C,and D, disclosed that, spatially, the temporal sequence ofdepolarizing events was the primary auditory cortex, hip-pocampus, and frontal cortex.

3.1.3. Evoked gamma oscillations

Figure 3 demonstrates that the tone stimulation evokesgamma frequency (the 30–200 Hz band) oscillations thatare concentrated mainly within the 30–50 Hz band, and thatthese oscillations are embedded within the wide-band signalwaveforms (0–200 Hz). When the group averages of evokedgamma oscillation were computed, the above considerationsof the sound intensity effects and the consistency of neuralresponsiveness between the two subgroups hold for the time(0–600 ms)–frequency (0–200 Hz) domain distributions ofpower densities, calculated from the same, high-pass fil-tered (above 30 Hz) single sweeps of signal data (Fig. 4Aand B). In all the three forebrain regions studied, the peak ofthe sensory stimulation-induced gamma band activity wasrestricted approximately to the 35–40 Hz frequency range.However, both in the primary auditory cortex and in thefrontal cortex, the activation fields involved tapering tailsextending near the frequency of 200 Hz and were comet-like in shape. In the hippocampus, the corresponding tailswere cut short at the frequency of approximately 100 Hz,and the corresponding activation fields were oval shaped.These pattern differences were disclosed when the unifiedscalings over the three brain structures were applied. Thismeant that the power density scalings of the data maps fromthe different brain regions were fitted to correspond to theintensity of the region-specific baseline EEG (obtainedfrom the prestimulus periods; 30–70 Hz range considered).

3.2. Association between forebrain tone responsiveness and AGS susceptibility

Figure 5 presents the evoked potential values of eachbrain structure against the AGS onset latencies of each sub-

ject. The evoked response values are expressed as normal-ized to the variable’s largest value in the group. The fittingsof both the linear regressions and Boltmann’s sigmoid non-linear regressions on the different sets of data points wereevaluated. In the primary auditory cortex and frontal cortex,Bolzmann’s sigmoid saturation functions expressed better

r

2

-values than the linear regressions did. In these structures,linear regressions were poorly fitted (0.03

<

r

2

<

0.48),whereas sigmoid saturation models were much better fitted,showing

r

2

-values of 0.54 to 0.84 (except for the responseamplitude-variable in the frontal cortex, where

r

2

5

0.40).In the hippocampus, the goodness of fit of the linear andnonlinear sigmoid regressions was essentially similar to the

r

2

-values of 0.64 to 0.76. In the hippocampus, the sigmoidsaturation plots were accordingly less steep compared to theprimary auditory or frontal cortices (see Fig. 5).

Figure 6 presents the averaged tone responsiveness of thethree forebrain structures in relation to the AGS onset la-tency, within the population of eight AGS-prone rats. Here,too, Bolzmann’s sigmoid regression models exhibited goodfittings (0.59

<

r

2

<

0.91) for the three different variablesof the evoked responses. Negative saturation curves appliedfor the response amplitude and slope, and the positive satu-ration function applied for the response peak latency. Over-all, these saturation profiles bore a resemblance to those ofthe individual forebrain structures (compare Figs. 5 and 6).As in the individual forebrain structures, the linear associa-tion (0.45

<

r

2

<

0.60) did not characterize the tone respon-siveness versus the AGS susceptibility relationship for thedata sets of the combined brain regions as well as the non-linear Boltzmann’s sigmoid regressions did (Fig. 6).

3.3. Effects of a single AGS on forebrain tone responsiveness

The control handling or the induction of an AGS had noeffects on any properties of the evoked responses in the pri-mary auditory cortex, hippocampus, or frontal cortex. Thelack of effects became apparent for the averaged response

Fig. 2. The group averages of the amplitude, slope, and latency components of the tone-evoked responses in the primary auditory cortex (A), hippocampus(H), and frontal cortex (F). (A) The baseline averages of the eight animals. Symbols: s, p , 0.05 when compared to the next lower sound intensity; *p , 0.05when compared to the lowest stimulus intensity. (B) The conditions before the control handling (group 1, white bars) or induction of a generalized AGS(group 2, white bars) and 15 min after these handlings (black bars). Note the lack of effects of either handling. The groupings of parts A and B correspond tothose presented in Figs. 1 C and D, respectively.

302



303

waveforms (Fig. 1D), the intensity of the gamma (30–200Hz) frequency oscillations of the evoked potentials duringthe time period of 600 ms (Fig. 4B), and the middle-latencyvariables of the evoked potentials (Fig. 2B).

4. Discussion

The field potential waveforms of tone-evoked responseswhich were measured in the present study from the stratumradiatum layer of the hippocampal CA1 area, layers II-IV ofthe primary auditory cortex, and frontal association cortexagree with those descriptions provided in the previous re-ports on these structures in rodents [62–68]. The compari-

sons of the excitability measures of neuronal populations toacoustic stimulation from these electrophysiologically char-acterized structures with the AGS susceptibility of eachsubject revealed the inverse Bolzmann’s sigmoidal associa-tions between the amplitude or slope components of thetone-evoked responses and the onset latency of AGS. Theconverse association for the response latency for the threedifferent forebrain structures appeared. These relationshipsfor the frontal and primary auditory cortices were close toeach other, whereas the hippocampus differed from these byshowing a less steep angle of saturation. In addition, overall,the saturation plots of the combined responsiveness of theprimary auditory cortex, hippocampus, and frontal cortexshowed similar patterns of saturation functions in relation to

Fig. 3. Acoustic stimulus-evoked gamma-frequency oscillations (30–200 Hz). The tone stimulus (5 ms, 98 dB, 8 kHz) delivery (arrow) evokes the 30–50 Hzband-concentrated oscillations (middle waveforms, and the bottom power density), which are embedded within the wide-band (0–200 Hz) responses (topwaveforms). The examples of synchronous records are shown for the primary auditory cortex (A), hippocampus (H), and frontal cortex (F). Below are shownthe power density spectra for the marked 275-ms segments of the wide-band (0–200) waveform signals. Note the stimulation-evoked increase of gamma fre-quency (30–200 Hz) powers centering at about 40 Hz.

Fig. 4. The grand group averages of power density maps over the time-frequency domains in the primary auditory cortex (A), hippocampus (H), and frontalcortex (F) with the increments of sound intensity. The time window of 600 ms and the frequency range of 0–200 Hz are depicted. Arrows mark the momentsof the 1.5-ms tone-pulse delivery. The groupings of parts A and B correspond to those presented in Fig. 1D. Note the response correspondence between thetwo subgroups during the baseline conditions in part A and left-hand side of part B, and the lack of effects of the subsequent control handling or the inductionof an AGS as shown in the right-hand side of part B.

304


AGS susceptibility to those that these structures establishedindividually.

Certain facts would support the idea that these correla-tions were determined by the structure-specific physiologicalfactors. First, the timing of depolarization events of re-sponses between the frontal and primary auditory corticesdiffered by 12 ms, but similar types of evoked response-AGS susceptibility relationships were established for thesecortical areas. Neural excitability and AGS susceptibility re-lationships for these structures were, thus, unlikely, due tothe volume conduction of field potentials from any source.Second, the frontal cortex depolarization peak followed byonly 1.2 ms that in the hippocampus, but the saturation plotsof these structures differed more in shape than in the abovecomparison. Third, during the baseline conditions, in all thebrain areas investigated, the group average increments of

about 40% in the response size following the increasing ofstimulus intensity (from 79 to 105 dB) were measured at astatistical confidence of

p , 0.003, but, at its height, thereappeared almost 400% intersubject differences in the corre-sponding variables which, thereby, could be surmised to bemeasured at a still better level of assurance. The associationsdemonstrated by the present study would suggest that thesediscrete forebrain cortical areas are related to the AGS erup-tion susceptibility in genetically epilepsy-prone KM-rats.

At present, there is a consensus that the neural track ofthe lateral lemniscus bundle, central nucleus of the IC, ex-ternal nucleus of the IC, deep layers of the SC, reticularispontis oralis nucleus, the periaqueductal gray of the hind-brain and spinal cord is involved in the generation of AGSs[14,15,69]. In other words, AGSs can be blocked with mid-/hindbrain-localized lesions of these structures [14,15], but

Fig. 5. The relationships between the amplitude, slope, and latency components of the evoked responses from the different forebrain structures and the AGSonset latencies for the eight rats. The Bolzmann’s sigmoidal saturation plots that were generated for the data sets of the frontal and primary auditory corticeswere close to each other. Those plots differed from that in the hippocampus where a more gently sloping relationship applied. Symbols S and L denote Bolz-mann’s nonlinear sigmoid regression and linear regression, respectively. For the comparison, the r-values and two-tailed p-values of the Pearson linear corre-lation test were in line with the linear regression results; primary auditory cortex (r: 20.56, 20.49, 0.18; p: 0.186, 0.265, 0.693), hippocampus (r: 20.87,20.80, 0.83; p: 0.005, 0.017, 0.011), frontal cortex (r: 20.39, 20.54, 0.70; p: 0.335, 0.170, 0.056); the sequence of numbers corresponds to the amplitude,slope, and latency variables.

A. Valjakka et al. / Physiology & Behavior 70 (2000) 297–309 305

not by cutting the connections above the IC [2]. Also, con-tradicting the suggestions of the present data but in line withthe studies referred to above, it has been shown that the mi-croinjection of moderate doses, which are effective in theIC, of competitive NMDA-receptor antagonists, AP7 andCPP, into the hippocampus does not affect AGS susceptibil-ity in Sprague–Dawley rats [9].

However, in AGS-prone Sprague–Dawley rats, the cen-tral nucleus of the IC and deep layers of the SC show, para-doxically, reduced excitability to acoustic stimulation atmoderate intensities [11,22], and the external nucleus of theIC shows increased neural responsiveness only at stimula-tion intensities near the threshold for AGS induction [70].The midbrain reticular formation is the only lower brain siteexpressing the outstanding AGS strain-related rise in neuralexcitability as shown in that rat strain [71]. On the otherhand, multiple demonstrations of cellular, neurochemical,and physiological changes in the hippocampal, thalamic,and neocortical fields in AGS-prone rats, which alterationsmay be supposed to render these areas more excitable, havebeen reported ([25,29,37,38,40,41,43–46]; see the Introduc-tion for further details). Accordingly, the AGS susceptibil-ity predisposing genetic abnormalities can be considered tobe as frequent in the discrete forebrain areas, as they are inthe brain stem structures. It, thus, may be hypothetized thatthe mere comparison of AGS-prone and -resistant popula-tions in relation to the differences within discrete brainstructures would not suggest the sole role of the lower brainareas in this seizure model.

On the other hand, neither could this kind of comparison,between the AGS-prone/resistant populations resolve the pro-pensity for seizures within the AGS-prone population of na-tive stage, freely behaving animals. The reasons for this aretwofold. First, there exist abundant and complex ascending/descending interareal connections between the brain areasthat are responsive to sound stimulation [15,22,51,62,64–66,72–81]. Second, if AGS-specific genetic abnormalities

were restricted, for example, only to the brain stem network,the individual discrete forebrain areas could, however, stillhave an important role in increasing the sensory excitation to/within these structures becoming uncontrollable neural over-excitation during the process leading to the generalized AGS.The present data would favor the latter hypothesis.

Considering the distributed acoustic and sensory responsesystem of the brain [83,84], which was demonstrated by thepresent study for the hippocampus, primary auditory cortex,and frontal cortex, the respective discrete forebrain systemsmay be surmised to exert at least some modulatory influencesupon the lower AGS structures of the brain because they arereciprocally connected with them. Several parallel feedbackprojection pathways from both the limbic and neocorticalstructures of the forebrain to the spinal cord motor neuronsystems (Fig. 7 ), which are ultimately responsible for the ste-reotyped muscle contractions during the AGSs [69], havebeen established. Most of these pathways are multisynapticseries of tracks (see Fig. 7). They involve the corticobulbartract, the tract of brachium pontis, and the reticulospinal tract,the last of which consists of projections from both the mid-and hindbrain reticular formations into the spinal cord [51].Another tract, the corticospinal pathway, projects directlyfrom the neocortex to the spinal cord motor neurons [51].Hence, the stimulatory events of high-frequency (gamma) orlow-frequency (middle-latency) oscillations of acoustic re-sponses, documented in the present study, should be effec-tively transmitted from forebrain to lower brain structures.Support for this is that the electrical stimulation of theamygdala of AGS-prone rats initiates seizure patterns that re-semble the brain stem-governed AGSs [48].

Finally, if there appeared some differences between theAGS predisposing efficacy of the different forebrain sys-tems, they might also respond with different intensities tothe excitation of generalized AGS. In fact, both in AGS-prone rats [35,85,86] and mice [87,88], a single AGS hasbeen reported to induce changes in the cortical levels of

Fig. 6. The relationships between the amplitude, slope, and latency components of the evoked responses for the combination of the different forebrain struc-tures and the AGS onset latencies within the group of eight rats. Symbols S and L denote Bolzmann’s nonlinear sigmoid regression and linear regression,respectively. For the comparison, the r-values and two-tailed p-values of the Pearson linear correlation test were in line with the linear regression results;amplitude (r: 20.678; p: 0.064), slope (r: 20669; p: 0.070), latency (r: 0.771; p: 0.025).

306 A. Valjakka et al. / Physiology & Behavior 70 (2000) 297–309

amino acids and other neurotransmitters, and the metabolicrate of glucose, persisting for several hours. In the KMstrain of rats, a behavioral consequence of an AGS is thethreshold elevation of bicuculline-induced seizure, which ismaximal 15 min after a AGS [61]. In the present study, theinduction of a single AGS had no effects upon the middle-latency or gamma components of the tone-evoked responses

in the hippocampus, frontal cortex, or auditory cortex, whenassessed 15 min after the AGS period. Despite the posedpresumption described above, the current result is in fullagreement with a previous series of studies [89–93], inwhich the effects of a single electroconvulsive shock on thecortically or subcortically evoked potentials induced by dif-ferent modalities of sensory stimulation, such as sound, were

Fig. 7. The major auditory projection pathways across the spinal cord, hindbrain, midbrain, and forebrain structures. Substantial auditory projections are pro-vided for the amygdala [51, 72, 73, 82] , hippocampus [51, 62, 74, 75], medial geniculate body of the thalamus [51, 64, 66, 76, 79–81], IC [51, 71, 78], SC[15, 22], frontal association cortex [51, 94], primary auditory cortex and its secondary belt regions [65, 66, 76, 77, 79], inferior temporal association cortex,and inferior parietal lobule [51]. In the AGS mechanisms, the following successive series of projection pathways have been considered to play a crucial role:the lateral lemniscus projection pathway, originating, for example, from the cochlear nuclei, into the central nucleus of the IC, which projects to the externalnucleus of the IC [95] that provides afferents to deep layers of the SC, and that finally send afferents via pontine reticular formation to the spinal cord motorneurons [15] (see the tract depicted). Besides the pontine reticular formation, several forebrain areas also send feedback projections into the spinal cord. Thehippocampal–subiculum–entorhinal area projects via the rostrocaudally arching continuum of fornix-medial forebrain bundles straight to the hypothalamusand via the fornix afferents to the septum, which then send axons to the hypothalamus. The hypothalamus, in turn, is the origin of a marked innervation of themidbrain reticular formation that innervates the hindbrain reticular formation, which finally projects through the reticulospinal tract to the spinal cord. Theneocortex projects within the corticopontine tract to the pons, which sends axons to the cerebellar cortex via the tract of the brachium pontis and, finally, thedeep cerebellar nuclei innervate the mid- and hindbrain reticular formations, which are the origins of the reticulospinal tract, as above. The neocortex alsodirectly innervates the hindbrain reticular formation and, via the corticospinal tract, the spinal cord motor neurons (for these descriptions see [51]). The sagit-tal section depicted represents the range of 1–3.5 mm lateral from the midline, and the horizontal section represents the level of 25.10 mm from the bregma.


investigated. It appeared that responses invariably recoveredto the normal within a few minutes after the seizure period.

In summary, the present results suggest that the differentforebrain structures are involved in the induction mecha-nisms of AGS within the AGS-prone population of KMWistar rats. That would mean that the acoustic responsesensitivity of the association (frontal cortex), multimodal(hippocampus) and primary sensory (auditory cortex area41) areas of the brain is related to the induction sensitivityof AGS with that sensory modality.

In general, the significance of the present physiologicaldata, obtained from seizure-prone animals, would be its im-plication that the variation of forebrain responsiveness,whether it is either due to the AGS susceptibility-related ge-netic alterations or not, can play a role in the initiation ofbrain stem-governed acoustic seizures within the populationof epilepsy prone subjects. This could be understood be-cause of the abundant projections between the limbic/non-limbic cortical areas and the primary epileptic foci of thebrainstem. Hence, although the forebrain sensory respon-siveness of seizure-prone animals was not genetically andphysiologically abnormal compared to the nonepileptic con-trols, these brain areas could, in theory, possess some inter-subject-related variations in their excitatory impact upon theprimary epileptic foci of the brain stem, and thus on theAGS induction.

Acknowledgments

The grant support from the Academy of Finland to L.T.is gratefully acknowledged. We are also indebted to Mr.Aapo Olkkonen for his valuable technical assistance, and toWilliam Ansell for revising the language of the manuscript.

References

[1] Bagri A, Sander G, Di-Scala G. Effects of unilateral microinjectionsof GABAergic drugs into the inferior colliculus on auditory evokedpotentials and on audiogenic seizure susceptibility. Exp Neurol 1989;104:82–7.

[2] Bagri A, Tomaz C, Brandao ML, Carrive P. Increased susceptibilityof detelencephalated rats to audiogenic seizures induced by microin-jection of bicuculline into the inferior colliculus. Braz J Med Biol Res1989;22:1361–70.

[3] Browning RA, Lanker ML, Faingold CL. Injections of noradrenergicand GABAergic agonists into the inferior colliculus: effects an audio-genic seizures in genetically epilepsy-prone rats. Epilepsy Res 1989;4:119–25.

[4] De Sarro G, De Sarro A, Meldrum BS. Anticonvulsant action of 2-chloroadenosine injected focally into the inferior colliculus and sub-stantia nigra. Eur J Pharmacol 1991;194:145–52.

[5] Faingold CL, Gehlbach G, Caspary DM. Decreased effectiveness ofGABA-mediated inhibition in the inferior colliculus of the geneti-cally epilepsy-prone rat. Exp Neurol 1986;93:145–59.

[6] Faingold CL, Marcinczyk MJ, Casebeer DJ, Randall ME, Arneric SP,Browning RA. GABA in the inferior colliculus plays a critical role incontrol of audiogenic seizures. Brain Res 1994;640:40–7.

[7] Faingold CL, Millan MH, Boersma CA, Anderson CA, Meldrum BS.Induction of audiogenic seizures in normal and genetically epilepsy-

prone rats following focal microinjection of an excitant amino acid intoreticular formation and auditory nuclei. Epilepsy Res 1989;3:199–205.

[8] Faingold CL, Millan MH, Boersma CA, Meldrum BS. Excitant aminoacids and audiogenic seizures in the genetically epilepsy-prone rat. I.Afferent seizure initiation pathway. Exp Neurol 1988;99:678–86.

[9] Faingold CL, Narituoku DK. The genetically epilepsy-prone rat: neu-ronal networks and actions of amino acid neurotransmitters. In: Fain-gold CL, Fromm GH, editors. Drugs for control of epilepsy: actionson neuronal networks involved in seizure disorders. Boca Raton, FL:CRC Press, 1992. pp. 277–308.

[10] Faingold CL, Naritoku DK, Copley CA, Randall ME, Riaz A, Ander-son CA, Arneric SP. Glutamate in the inferior colliculus plays a criticalrole in audiogenic seizure initiation. Epilepsy Res 1992;13:95–105.

[11] Faingold CL, Randall ME, Anderson CA. Blockade of GABA uptakewith tiagabine inhibits audiogenic seizures and reduces neuronal fir-ing in the inferior colliculus of the genetically epilepsy-prone rat. ExpNeurol 1994;126:225–32.

[12] Millan MH, Meldrum BS, Faingold CL. Induction of audiogenic sei-zure susceptibility by focal infusion of excitant amino acid and bicu-culline into the inferior colliculus of normal rats. Exp Neurol 1986;91:634–9.

[13] Tang E, Yip PK, Chapman AG, Jane DE, Meldrum BS. Prolongedanticonvulsant action of glutamate metabotropic receptor agonist ininferior colliculus of genetically epilepsy-prone rats. Eur J Pharmacol1997;327:109–15.

[14] Browning RA VII. Neuroanatomical localization of structures re-sponsible for seizures in the GEPR: lesion studies. Life Sci 1986;39:857–67.

[15] Ribak CE, Khurana V, Lien NT. The effect of midbrain collicularknife cuts on audiogenic seizure severity in the genetically epilepsy-prone rat. J Brain Res 1994;35:303–11.

[16] Browning RA, Nelson DK, Mogharreban N, Jobe PC, Laird HE II.Effect of midbrain and pontine tegmental lesions on audiogenic sei-zures in genetically epilepsy-prone rats. Epilepsia 1985;26:175–83.

[17] Faingold CL, Anderson CA. Loss of intensity-induced inhibition ininferior colliculus neurons leads to audiogenic seizure susceptibilityin behaving genetically epilepsy-prone rats. Exp Neurol 1991;113:354–63.

[18] Hirsch E, Maton B, Vergnes M, Depaulis A, Marescaux C. Reciprocalpositive transfer between kindling of audiogenic seizures and electri-cal kindling of inferior colliculus. Epilepsy Res 1993;15:133–9.

[19] Maxson SC, Sze PY. Electroencephalographic correlates of audio-genic seizures during ethanol withdrawal in mice. Psychopharmacol(Berlin) 1976;47:17–20.

[20] Millan MH, Meldrum BS, Boersma CA, Faingold CL. Excitantamino acids and audiogenic seizures in the genetically epilepsy-pronerat. II. Efferent seizure propagating pathway. Exp Neurol 1988;99:687–98.

[21] N’Gouemo P, Faingold CL. Periaqueductal gray neurons exhibit in-creased responsiveness associated with audiogenic seizures in the ge-netically epilepsy-prone rats. Neuroscience 1998;84:619–25.

[22] Faingold CL, Randall ME. Neurons in the deep layers of superior col-liculus play a critical role in the neuronal network for audiogenic sei-zures: mechanisms for production of wild running behavior. BrainRes 1999;815:250–8.

[23] Ribak CE, Manio AL, Navetta MS, Gall CM. In situ hybridization forc-fos mRNA reveals the involvement of the superior colliculus in thepropagation of seizure activity in genetically epilepsy-prone rats. Ep-ilepsy Res 1997;26:397–406.

[24] Ribak CE, Byun MY, Riuz GT, Reiffenstein RJ. Increased levels ofamino acid neurotransmitters in the inferior colliculus of the geneti-cally epilepsy-prone rat. Epilepsy Res 1988;2:9–13.

[25] Lasley SM. Role of neurotransmitter amino acids in seizure severityand experience in the genetically epilepsy-prone rat. Brain Res 1991;560:63–70.

[26] Browning RA, Wade DR, Marcinczyk M, Long GL, Jobe PC. Re-gional brain abnormalities in norepinephrine uptake and dopamine

308 A. Valjakka et al. / Physiology & Behavior 70 (2000) 297–309

beta-hydroxylase activity in the genetically epilepsy-prone rat. JPharmacol Exp Ther 1989;249:229–35.

[27] Jobe PC, Mishra PK, Browning RA, Wang G, Adams–Curtis LE, KoKH, Dailey W. Noradrenergic abnormalities in the genetically epi-lepsy-prone rat. Brain Res Bull 1994;35:493–504.

[28] Lauterborn JC, Ribak CE. Differences in dopamine beta-hydroxylaseimmunoreactivity between the brains of genetically epilepsy-proneand Sprague–Dawley rats. Epilepsy Res 1989;4:161–76.

[29] Dailey JW, Mishra PK, Ko KH, Penny JE, Jobe PC. Serotonergic ab-normalities in the central nervous system of seizure-naive and geneti-cally epilepsy-prone rats. Life Sci 1992;50:319–26.

[30] Statnick MA, Dailey JW, Jobe PC, Browning RA. Abnormalities in5-HT1A and 5-HT1B receptor binding in severe-seizure genetically ep-ilepsy-prone rats (GEPR-9s). Neuropharmacology 1996;35:111–8.

[31] Statnick MA, Dailey JW, Jobe PC, Browning RA. Abnormalities inbrain serotonin concentration, high-affinity uptake, and tryptophanhydroxylase activity in severe-seizure genetically epilepsy-prone rats.Epilepsia 1996;37:311–21.

[32] Meldrum BS. GABAergic mechanisms in the pathogenesis and treat-ment of epilepsy. Br J Clin Pharmacol 1989;27:3S–11S.

[33] Ribak CE, Lauterborn JC, Navetta MS, Gall CM. The inferior collicu-lus of GEPRs contains greater numbers of cells that express glutamatedecarboxylate (GAD67) mRNA. Epilepsy Res 1993;14:105–13.

[34] Roberts RC, Ribak CE, Oertel WH. Increased numbers of GABAer-gic neurons occur in the inferior colliculus of an audiogenic model ofgenetic epilepsy. Brain Res 1985;361:324–38.

[35] Chapman AG, Faingold CL, Hart GP, Bowker HM, Meldrum BS.Brain regional amino acid levels in seizure susceptible rats: changesrelated to sound-induced seizures. Neurochem Int 1986;8:273–79.

[36] Faingold CL, Travis MA, Gehlbach TG, Hoffmann WE, Jobe PC,Laird HE, Caspary DM. Neuronal response abnormalities in the infe-rior colliculus of the genetically epilepsy-prone rat. Electroencepha-logr Clin Neurophysiol 1986;63:296–305.

[37] Lehmann A, Sandberg M, Huxtable RJ. In vivo release of neuroactiveamines aminoacids from the hippocampus of seizure-resistant andseizure-susceptible rats. Neurochem Int 1986;8:513–20.

[38] Evans MS, Viola–McCabe KE, Caspary DM, Faingold CL. Loss ofsynaptic inhibition during repetitive stimulation in genetically epi-lepsy-prone rats (GEPR). Epilepsy Res 1994;18:97–105.

[39] Evans MS. Membrane and synaptic properties of genetically epi-lepsy-prone rat hippocampal neurons. Epilepsia 1993;34:76.

[40] Evans MS, McCabe KE, Caspary DM, Faingold CL, Kalita S, PencekTL. Paired pulse facilitation is increased in genetically epilepsy-prone rat (GEPR) hippocampus. Neurology 1991;41:404.

[41] Evans MS, McCabe KE, Faingold CL, Caspary DM. Repetitive syn-aptic stimulation evokes increased excitatory responses in geneticallyepilepsy-prone rat hippocampus. Epilepsia 1991;32:41.

[42] Li Y, Evans MS, Faingold CL. Inferior colliculus neuronal membraneand synaptic properties in genetically epilepsy-prone rats. Brain Res1994;660:232–240.

[43] Savage DD, Mills SA, Jobe PC, Reigel CE. Elevation of naloxone-sensitive 3H-dihydromorphine binding in hippocampal formation ofgenetically epilepsy-prone rats. Life Sci 1988;43:239–46.

[44] Onodera K, Tuomisto L, Tacke U, Airaksinen M. Strain differencesin regional brain histamine levels between genetically epilepsy-proneand resistant rats. Methods Find Exp Clin Pharmacol 1992;14:13–16.

[45] Tuomisto L, Ylinen M, Onodera K, Tacke U, Airaksinen M. Compar-ison of regional brain histamine and tele-methylhistamine levels ingenetically epilepsy-prone rats and in rats resistant to epilepsy. Meth-ods Find Exp Clin Pharmacol. 1996;18:155–9.

[46] Jobe PC, Dailey JW, Reigel CE. Noradrenergic and serotonergic de-terminants of seizure susceptibility and severity in genetically epi-lepsy-prone rats. Life Sci 1986;39:775–82.

[47] Akbar MT, Rattray M, Williams RJ, Chong NWS, Meldrum BS. Reduc-tion of GABA and glutamate transporter messenger RNAs in the severe-seizure genetically epilepsy-prone rat. Neuroscience 1998;85:1235–51.

[48] Coffey LL, Maarten EA, Reith MEA, Chen N-H, Mishra PK, Jobe

PC. Amygdala kindling of forebrain seizures and the occurrence ofbrainstem seizures in genetically epilepsy-prone rats. Epilepsia 1996;37:188–97.

[49] Savage DD, Reigel CE, Jobe PC. Angular bundle kindling is acceler-ated in rats with a genetic predisposition to acoustic stimulus-inducedseizures. Brain Res 1986;376:412–5.

[50] Savage DD, Reigel CE, Jobe PC IX. The development of kindled sei-zures is accelerated in the genetically epilepsy-prone rat. Life Sci1986;39:879–86.

[51] Nauta JHW, Feirtag M. Fundamental neuroanatomy. New York: WHFreeman and Company, 1986.

[52] Hirsch E, Danober L, Simler S, Pereira-de-Vasconcelos A, Maton B,Nehlig A, Marescaux C, Vergnes M. The amygdala is critical for sei-zure propagation from brainstem to forebrain. Neuroscience 1997;77:975–84.

[53] Hirsch E, Maton B, Vergnes M, Depaulis A, Marescaux C. Positivetransfer of audiogenic kindling to electrical hippocampal kindling inrats. Epilepsy Res 1992;11:159–66.

[54] McCown TJ, Greenwood RS, Breese GR. Inferior collicular interac-tions with limbic seizure activity. Epilepsia 1987;28:234–41.

[55] Naritoku DK, Mecozzi LB, Aiello MT, Faingold CL. Repetition ofaudiogenic seizures in genetically epilepsy-prone rats induces corticalepileptiform activity and additional seizure behaviors. Exp Neurol1992;115:317–24.

[56] N’Gouemo P, Faingold CL. Audiogenic kindling increases neuronalresponses to acoustic stimuli in neurons of the medial geniculate bodyof the genetically epilepsy-prone rat. Brain Res 1997;76:217–24.

[57] Simler S, Ciesielski L, Clement J, Rastegar A, Mandel P. Long last-ing effects of audiogenic seizures on synaptosomal neurotransmitteramino acids in Rb mice. Neurochem Res 1994;19:555–61.

[58] Tacke U, Björk E, Tuomisto J. The effect of changes in sound pres-sure level and frequency on the seizure response of audiogenic sei-zure susceptible rats. J Pharmacol Methods 1984;11:279–90.

[59] Paxinoss G, Watson C. The rat brain in stereotaxic coordinates. NewYork: Academic Press, 1986.

[60] Reigel CE, Dailey JW, Jobe PCI. The genetically epilepsy-prone rat:an overview of seizure-prone characteristics and responsiveness toanticonvulsant drugs. Life Sci 1986;39:763–774.

[61] Tacke U, Paananen A, Tuomisto J. Seizure thresholds and their pos-tictal changes in audiogenic seizure (AGS)-susceptible rats. Eur JPharmacol 1984;104:85–92.

[62] Brankack J, Buzsáki G. Hippocampal responses evoked by tooth pulpand acoustic stimulation: depth profiles and effect of behavior. BrainRes 1986;378:303–14.

[63] Barth DS, Di S. Three-dimensional analysis of auditory-evoked po-tentials in rat neocortex. J Neurophysiol 1990;64:1527–36.

[64] Barth DS, Di S. The functional anatomy of middle latency auditoryevoked potentials. Brain Res 1991;565:109–15.

[65] Barth DS, Goldberg N, Brett B, Di S. The spatiotemporal organiza-tion of auditory, visual, and auditory-visual evoked potentials in ratcortex. Brain Res 1995;678:177–90.

[66] Brett B, Di S, Watkins L, Barth DS. A horseradish peroxidase study ofparallel thalamocortical projections responsible for the generation ofmid-latency auditory-evoked potentials. Brain Res 1994;647:65–75.

[67] Di S, Barth DS. Binaural vs. monaural auditory evoked potentials inrat neocortex. Brain Res 1993;630:303–14.

[68] Yoshida M, Lowry LD, Liu JJC, Kaga K. Auditory 40-Hz responsesin the guinea pig. Am J Otolaryngol 1984;5:404–10.

[69] Faingold CL. Locomotor behaviors in generalized convulsions are hi-erarchically driven from specific brain-stem nuclei in the networksubserving audiogenic seizure. Ann NY Acad Sci 1988;860:566–9.

[70] Chakravarty DN, Faingold CL. Increased responsiveness and failureof habituation in neurons of the external nucleus of inferior colliculusassociated with audiogenic seizures of the genetically epilepsy-pronerat. Exp Neurol 1996;141:280–6.

[71] Faingold CL, Randall ME. Pontine reticular formation neurons ex-hibit a premature precipitous increase in acoustic responses prior to


audiogenic seizures in genetically epilepsy-prone rats. Brain Res1995;704:218–26.

[72] Bordi F, Ledoux JE. Sensory tuning beyond the sensory system: aninitial analysis of auditory response properties of neurons in the lat-eral amygdaloid nucleus and overlying areas of the striatum. J Neuro-sci 1992;12:2493–503.

[73] Bordi F, LeDoux JE. Response properties of single units in areas ofrat auditory thalamus that project to the amygdala. II. Cells receivingconvergent auditory and somatosensory inputs and cells antidromicallyactivated by amygdala stimulation. Exp Brain Res 1994;98:275–86.

[74] Buzsaki G, Penttonen M, Bragin A, Nadasdy Z, Chrobak J. Possiblephysiological role of the perforant path-CA1 projection. Hippocam-pus 1995;5:41–146.

[75] Deadwyler SA, West JR, Cotman CW, Lynch G. Physiological stud-ies of the reciprocal connections between the hippocampus and en-torhinal cortex. Exp Neurol 1975;49:35–57.

[76] Di S, Barth DS. The functional anatomy of middle-latency auditoryevoked potentials: thalamocortical connections. J Neurophysiol 1992;68:425–31.

[77] Hu B, Senatorov V, Mooney D. Lemniscal and non-lemniscal synap-tic transmission in rat auditory thalamus. 1994;479:217–31.

[78] Reez G, Ehret G. Inputs from three brainstem sources to identified neu-rons of the mouse inferior colliculus slice. Brain Res 1999;816:527–43.

[79] Vaughan DW. Thalamic and callosal connections of the rat auditorycortex. Brain Res 1983;260:181–9.

[80] Winer JA. The functional architecture of the medial geniculate bodyand the primary auditory cortex. In: Webster DB, Popper AN, FayRR, editors. The mammalian auditory pathway: Neuroanatomy. NewYork: Springer Verlag, 1992. pp 222–409.

[81] Winer JA, Larue DT. Patterns of reciprocity in auditory thalamocorti-cal and corticothalamic connections: study with horseradish peroxi-dase and autoradiographic methods in the rat medial geniculate body.J Comp Neurol 1987;257:282–315.

[82] Zhou SC, Lu XY, Yin HZ. Study of inhibitory effect of amygdaloidstimulation on auditory response of medial geniculate body (MGB)and analysis of transmissive pathway of the said effect. Sci Sin B.1983;26:262–73.

[83] Basar E, Demiralp T. Fast rhythms in the hippocampus are a part ofthe diffuse gamma-response system. Hippocampus 1995;5:240–1.

[84] Demiralp T, Basar–Eroglu C, Basar E. Distributed gamma band re-sponses in the brain studied in cortex, reticular formation, hippocam-pus and cerebellum. Int J Neurosci 1996;84:1–13.

[85] Hayakawa H, Yokota N, Shimizu M, Nishida A, Yamawaki S. Re-peated treatment with electroconvulsive shock increases numbers ofserotonin1A receptors in the rat hippocampus. Biogenic Amines1993;9:295–306.

[86] Nehlig A, Pareira-de-Vanconcelos AP, Vergnes M, Boyet S, Mares-caux C. Interictal cerebral metabolic levels in Wistar rats sensitive toaudiogenic seizures. Brain Res 1996;724:97–102.

[87] Clement J, Ciesielski L, Simler S, Mandel P. Long lasting effect of asingle audiogenic seizure on GABA turnover rates and steady-statelevels. Neurochem Res 1989;14:445–53.

[88] Simler S, Hirsch E, Danober L, Motte J, Vergnes M, Marescaux C. c-fos expression after single and kindled audiogenic seizures in Wistarrats. Neurosci Lett 1994;175:58–62.

[89] Shaw NA. Effect of electroconvulsive shock on the somatosensoryevoked potential in the rat. Exp Neurol 1985;90:566–79.

[90] Shaw NA. Effect of electroconvulsive shock on the cervical evokedpotential in the rat. Exp Neurol 1986;91:646–9.

[91] Shaw NA. The auditory evoked potential in the rat—a review. ProgNeurobiol 1988;31:19–45.

[92] Shaw NA. The effects of electroconvulsive shock on the flash visualevoked potential in the rat. Electroencephalogr Clin Neurophysiol1997;104:180–7.

[93] Shaw NA. The effects of electroconvulsive shock on the short-la-tency somatosensory evoked potential in the rat. Brain Res Bull 1998;45:427–33.

[94] Hackett TA, Stepniewska I, Kaas JH. Prefrontal connections of theparabelt auditory cortex in macaque monkeys. Brain Res 1999;817:45–58.

[95] Chakravarty DN, Faingold CL. Aberrant neuronal responsiveness inthe genetically epilepsy-prone rat: acoustic responses and influencesof central neucleus upon the external nucleus of inferior colliculus.Brain Res 1997;761:263–70.

The relationship between audiogenic seizure (AGS) susceptibility and forebrain tone-responsiveness...

Documents

Transcript of The relationship between audiogenic seizure (AGS) susceptibility and forebrain tone-responsiveness...