Schizophrenia Research xxx (2014) xxx–xxx

SCHRES-06042; No of Pages 8

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Schizophrenia Research

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Histological correlates of N40 auditory evoked potentials in adult ratsafter neonatal ventral hippocampal lesion: animal modelof schizophrenia

A.L. Romero-Pimentel a,b, R.A. Vázquez-Roque b, I. Camacho-Abrego b, K.L. Hoffman a, P. Linares b,G. Flores b,⁎, E. Manjarrez b,⁎a Centro de Investigación en Reproducción Animal (CIRA), Universidad Autónoma de Tlaxcala-CINVESTAV, Tlaxcala, CP 90070, Méxicob Instituto de Fisiología, Benemérita Universidad Autónoma de Puebla, 14 Sur 6301, Col. San Manuel, Puebla, Puebla, CP 72570, México

⁎ Corresponding authors at: Instituto de Fisiología, Bende Puebla, 14 sur 6301, Col. San Manuel A.P. 406, C.PTel.: +52 22 22 29 5500x7326; fax: +52 22 22 33 4511.

E-mail addresses: gonzalo.flores@correo.buap.mx (G. Feliasmanjarrez@gmail.com, elias.manjarrez@correo.buap.

http://dx.doi.org/10.1016/j.schres.2014.09.0090920-9964/© 2014 Elsevier B.V. All rights reserved.

Please cite this article as: Romero-Pimentel, Ahippocampal lesion: animal model of..., Schi

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Article history:Received 9 July 2014Received in revised form 28 August 2014Accepted 4 September 2014Available online xxxx

Keywords:Auditory Evoked PotentialsN40 waveneonatal ventral hippocampus lesionschizophrenia

The neonatal ventral hippocampal lesion (NVHL) is an established neurodevelopmental ratmodel of schizophre-nia. Rats with NVHL exhibit several behavioral, molecular and physiological abnormalities that are similar tothose found in schizophrenics. Schizophrenia is a severe psychiatric illness characterized by profound distur-bances of mental functions including neurophysiological deficits in brain information processing. These deficitscan be assessed by auditory evoked potentials (AEPs), where schizophrenics exhibit abnormalities in amplitude,duration and latency of such AEPs. The aim of the present study was to compare the density of cells in the tem-poral cerebral cortex and the N40-AEP of adult NVHL rats versus adult sham rats. We found that rats with NVHLexhibit significant lower amplitude of the N40-AEP and a significant lower number of cells in bilateral regions ofthe temporal cerebral cortex compared to sham rats. Because the AEP recordings were obtained from anesthe-tized rats, we suggest that NVHL leads to inappropriate innervation in thalamic-cortical pathways in the adultrat, leading to altered function of cortical networks involved in processing of primary auditory information.

© 2014 Elsevier B.V. All rights reserved.

1. Introduction

The neonatal ventral hippocampal lesion (NVHL) is an establishedrat neurodevelopmentalmodel of schizophrenia. RatswithNVHLexhib-it several behavioral, molecular, and physiological abnormalities whichare similar to schizophrenia (for review see Tseng et al., 2009). TheNVHL model exhibits reduction in the number of GABAergic neuronsin many brain areas (Endo et al., 2007; Straub et al., 2007; Francoiset al., 2009), deficits in GABAergic neurotransmission (Endo et al.,2007 and Francois et al., 2009), sensitivity to NMDA antagonists (Al-Amin et al., 2000 and Tseng et al., 2007) and a reduction in the numberof neurons that integrate some of the part of the limbic system(Vázquez-Roque et al., 2012). Schizophrenia is a devastatingmental ill-ness that affects 1% of the world population. It is characterized by brainabnormalities and profound disturbances of mental functions (Harrisonand Weinberger, 2005). Patients with schizophrenia show severe neu-rophysiological deficits in brain information processing, not only at cog-nitive levels (Goldberg and Gold, 1995) but also at perceptual and

emérita Universidad Autónoma. 72570, Puebla, Pue., México.

lores),mx (E. Manjarrez).

.L., et al., Histological correlatezophr. Res. (2014), http://dx.d

sensory levels (Braff et al., 1991; Branner et al., 2009). Recently, we re-ported (Valdés-Cruz et al., 2012) that NVHL resulted in a decrease inthe absolute power of the parietal and occipital electroencephalograph-ic recordings (at 1–8 Hz, 9–14 Hz, and 15–30 Hz bands). Moreover, theNVHL rats also showed a reduction in exploratory behavior.

The N40waveform of the auditory evoked potential (AEP) in the ratwasfirst described by Knight et al. (1985). The rat N40-AEP is a negativecomponent that is recorded from the cortex 40 to 60msec following au-ditory stimulation (Adler et al., 1986; Boutros et al., 1997). The origin ofthe N40 is unknown but one possible source of this waveform has beenlocalized in the CA3 region of the hippocampus (Bickford-Wimer et al.,1990). This region receives glutamatergic input from the entorhinal cor-tex and cholinergic input from the medial septum (Insausti et al., 1997;Cenquizca and Swanson, 2007).

The rat N40-AEP hasmainly been employed for studyingmechanismsof sensory gating (De rojas et al., 2013; Okamoto et al., 2012; Chen et al.,2012; Swerdlow et al., 2012; Breier et al., 2010; Vohs et al., 2009; Zhouet al., 2008; Keedy et al., 2007; Hashimoto et al., 2005; Zheng et al.,2005; Siegel et al., 2005; Miyazato et al., 1999; Boutros et al., 1997;Boutros and Kwan1998; Johnson et al., 1998: Stevens et al., 1998; Flachet al., 1996; Shinba et al., 1996; Bickford and Wear, 1995; Campbellet al., 1995; Bickford andWear, 1995; Luntz-Leybman et al., 1992). Senso-ry gating can be defined as the ability of the brain to attenuate incomingirrelevant sensory stimuli (Freedman et al., 1987). Schizophrenic patients

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exhibit abnormalities in several characteristics of the AEP sensorial gating(For review see Patterson et al., 2008; Brockhaus-Dumke et al., 2008;Myles-Worsley et al., 2004). These alterations in sensory gating in schizo-phrenics are similar to those reported in rats with NVHL (Vohs et al.,2009; Swerdlow et al., 2012). However, in such studies the averaged am-plitude of the N40 auditory evoked potential has not been employed toexamine the integrity of networks underlying the processing of sensoryinformation in NVHL rats.

The above-mentioned studies suggest that theNVHL could disrupt thedevelopment and function of the circuitry involved in auditory sensorialprocessing. In this context, the purpose of the present studywas to exam-ine auditory processing abnormalities in NVHL rats, by characterizingN40-AEPs and the histological analysis of the temporal cerebral cortex.

Specifically, we hypothesized that the N40-AEP in NVHL-rats exhibitlower amplitude compared to the N40-AEP in sham rats, since a consis-tent characteristic of schizophrenics is the reduced amplitude in the au-ditory evoked potential (see Fig. 1 from Rosburg et al., 2008).Furthermore, we hypothesized that NVHL rats exhibit a significant re-duction in the density of cells located in the temporal cerebral cortexcompared with sham rats.

2. Materials and methods

2.1. Animals

We performed experiments in rats in accordance with the EuropeanCommunities Council Directive of 24November 1986 (86/609/EEC), the

Fig. 1. Schematic drawing of coronal sections illustrating area of the NVHL lesion as determineconstruction of the neuronal loss and gliosis in the hippocampus of the rat with themost widespand Watson (1986).

Please cite this article as: Romero-Pimentel, A.L., et al., Histological correlathippocampal lesion: animal model of..., Schizophr. Res. (2014), http://dx.d

guidelines contained in the National Institutes of Health Guide for theCare and Use of Laboratory Animals (85–23, revised in 1985) and the“Norma Oficial MexicanaNOM-062-ZOO-1999”. Moreover, the Instituteof Physiology from the Benemerita Universidad Autonoma de Puebla,Mexico, approved the present study. Pregnant Sprague–Dawley ratswere obtained at gestational Days 14–17 from our animal facilities.The rats were individually housed in a temperature and humidity con-trolled environment on a 12:12 h light–dark cycle with free access tofood and water. We strictly followed the same animal care proceduresas in our previous studies (Valdés-Cruz et al., 2012; Vázquez-Roqueet al., 2012).

2.2. Neonatal ventral hippocampal lesion (NVHL)

At postnatal day (PND) 7, male pups were randomly assigned to ei-ther sham or lesioned group. They were hypothermically anesthetizedand positioned on a modified platform (Sierra et al., 2009) fixed on astereotaxic apparatus (Narishige, Scientist Instrument Lab. SN-2 N).For the neonatal ventral hippocampal lesion (NVHL) an incision onthe skin overlaying the skull was made, and two 1 mm holes weredrilled. A needle connected to an infusion pump through a Hamilton sy-ringe was lowered into each ventral hippocampus coordinate: AP-3.0 mm, ML ± 3.5 relative to bregma and VD −4.9 relative to dura.Ibotenic acid (0.3 μL, 10 μg/μL; Sigma, St Louis, MO) in 0.15Mphosphatebuffer saline (PBS) pH7.4 or vehiclewas infused bilaterally at aflow rateof 0.15 μL/min. Pups were monitored and warmed before beingreturned to their cages. On PD21, the animals were weaned and a

d by Nissl-stained sections of the hippocampus of animals at a postpubertal age. Black, re-read lesion. Numbers indicate distance (mm) posterior from bregma according to Paxinos

es of N40 auditory evoked potentials in adult rats after neonatal ventraloi.org/10.1016/j.schres.2014.09.009

Fig. 2.Grand average of the N40 auditory evoked potential (AEP) amplitude versus the au-ditory stimulus intensity for sham (red circles) andNVHL (blues circles) rats. TheN40 is anAEP component occurring 40 to 60 msec following auditory stimulation. The horizontalline below the asterisk indicates that all the mean amplitude values of the N40-AEPfrom 90 dB to 120 dB between NVHL and sham rats were statistically significant different(Mann Whitney U-test, *p b 0.05).

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similar number of sham and lesioned ratswere placed in cages (four an-imals per cage). During the NVHL we strictly followed the same careprocedures as in our previous studies (Flores et al., 2005; Valdés-Cruzet al., 2012; Vázquez-Roque et al., 2012).

2.3. Recording of Auditory Evoked Potentials

2.3.1. Animal preparationAt PD 120–140, sham (n= 4) and lesioned rats (n= 6) thatweighed

between 350 and 400 g, were anesthetized with a mixture of isoflurane(20 %) and oxygen (80 %). The trachea was cannulated in order to ad-minister the anesthesia directly and to allow artificial ventilation, ifneeded. The right jugular veinwas cannulated in order to administer At-ropine (0.05 mg/kg) and Dexamethasone (2 mg/kg). Isoflurane waschanged to alpha-cholaroza/borax (60 mg/Kg/1ml) through the jugularvein after this was cannulated. The rats were placed in a stereotaxic ap-paratus. The skullcap of the rats was removed between lambda andbregma cranial suture. The meninges were removed and 12 electrodeswere placed on the surface of the exposed cerebral cortex. Auditorystimuli were delivered binaurally by means of a STIM2 system fromNeuroscan. Two plastic tubes included in the STIM2-earphones weregently introduced in the rat eardrum. The stimuli comprised a clickwith duration of one millisecond and 1Hz of frequency presentation. Itwas emitted at magnitudes of 70, 80, 90, 100, 110, 115 and 120 dB.For each magnitude the click was presented 64 times, therefore, intotal 448 stimuli were presented per rat.

2.3.2. Recordings and analysisThe AEPswere recorded using aNeuroscan Synamps 2 EEG amplifier

system from an array of 12 silver-silver chloride Ag/AgCl surface elec-trodes (200 micrometers of diameter). The reference was an Ag/AgClelectrode inserted into the surroundingmuscle tissue. This array of elec-trodes was designed in our laboratory and adapted to the synamps 2amplifier according to our previous reports (Manjarrez et al., 2005;Cuellar et al., 2009). All signals were digitalized without filtering in DCmode with a sample rate of 10 kHz, 24-bit A/D conversion and a DC-500 Hz band-pass filter. Further, all signals were off-line filtered from500Hz to 5 kHzwith the sameNeuroscan software. Processing includedsegmentation (0–150 ms before/after the stimuli were presented),baseline correction, artifact rejection and averaging. The N40-AEP,P80-AEP and N120-AEP components in the averaged signals were iden-tified (seemagenta arrows in Fig. 3B).We observed amaximal negativepeak around 50 ms (i.e., a N40-AEP), which was determined by identi-fying the most negative deflection between 40 and 60 ms. The ampli-tude of these AEP components were measured as indicated by thevertical green line in Fig. 3B. Latencies were measured from the timeof the stimulus onset to the peak of the maximal AEP negative peak asindicated by the horizontal green line in Fig. 3B. In order to perform astatistical analysis, the electrode located over the temporal hemisphere(which exhibited the maximal amplitude) was selected from the elec-trode array; subsequently from this unique electrode the averaging ofthe AEP was obtained. Since the data followed non-normal distributionand to compare latency and N40-AEP component among groups weused the Mann–Whitney U test.

2.3.3. Stereological analysisWe performed a stereological analysis of the brains of a subgroup of

the same rats employed in the AEP studies. After the AEP experiment, 5of the 6 NVHL rats and all 4 sham rats were deeply anesthetized with so-dium pentobarbital (75 mg/kg ip) and perfused through the heart with0.9% saline, followed by 4% paraformaldehyde in 0.1 M phosphate buffer.Forty-micrometer-thick coronal sections from the primary and secondaryauditory temporal cortex were obtained using a vibratome (model 2000;Leica). For stereological analysis of neuronal populations, briefly, sectionsweremounted on glass slides and stainedwith cresyl violet andwere an-alyzed with the optical dissector as previously described (Chana et al.,

Please cite this article as: Romero-Pimentel, A.L., et al., Histological correlatehippocampal lesion: animal model of..., Schizophr. Res. (2014), http://dx.d

2003; Kuczenski et al., 2007; Vázquez-Roque et al., 2012). Cellswere sam-pled within a volume in the primary and secondary auditory temporalcortex by optical sectioning, at a 10 μm distance, within the vibratomesection, using an Olympus BH2microscopewith a digital color camera at-tached to a DataCell computer-assisted image analysis system (Stereo In-vestigator System; MicroBrightField, Williston, VT) for stereology. Fromeach case, at least five random sections within a given area of about400 μm were analyzed, and results were averaged and expressed astotal number of cells per cubic millimeter.

3. Results

3.1. Verification of the lesion

All brains were examined under light microscopy for location of theibotenic acid lesion. Cresyl violet-stained sections obtained from adultNVHL animals revealed significant bilateral damage of the ventral hip-pocampus, with neuronal loss, atrophy, and apparent retraction of thehippocampal formation. The brains of the sham animals did not showany morphological alterations (Fig. 1).

3.2. Auditory Evoked Potential

The amplitude of the N40-AEP component increased for both groupswith the stimulation intensity of 80, 90, 95, 100, 110, 115, 120 dB, asshown in Fig. 2. Fig. 2 illustrates sigmoid curves obtained from averagingof the N40-AEP amplitude (for each auditory intensity we averaged 64samples) for four sham rats and six NVHL rats. This phenomena showsa Sigmoid distribution (2 parameters sigmoid adjustment test, R N 0.90,p b 0.001 for all the cases). Nevertheless, this intensity dependence wasaltered by NVHL rats across the stimulation range of 110, 115 and120 dB. At this range, the N40-AEP component amplitude did not in-crease, while that of the sham rats showed a clear increase. NVHL ratsshowed a decrease of the N40-AEP component in most cases, as com-pared with the sham animal (Fig. 2, 3, Table 1). Fig. 3 shows averaged re-cordings of AEP for sham (red traces) and NVHL (blue traces) rats. Notethat for 100 and 120 dB the NVHL rats exhibited N40-AEPs of lower am-plitude than those evoked in sham rats. Mann Whitney U-test indicatedthat these differences where significant at 90, 95, 100, 110, 115 and120 dB stimulation (P = b0.05, for all cases). By contrast, the latency ofthe N40-AEP component potential did not differ between the two groups(Table 2).

We include six tables with quantitative data for positive and nega-tive responses across the AEP recorded (N40, P80 and N120). As

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Fig. 3. Grand average of N40-AEP for Sham (red traces) and NVHL (blues traces) rats ob-tained after 80, 100 and 120 dB stimuli. The arrow indicates the time of application ofthe auditory stimuli.

Table 2The median, maximums and minimums of the N40-AEP latency for sham and NHVLgroups. Mann–Whitney U test statistics values are shown for sham group versus NVHLgroup latency differences.

StimulusIntensity (dB)

Sham NVHL U P

Median(ms)

Max/min(ms)

Median(ms)

Max/min(ms)

80 40.10 40.50/0 38.56 40.90/0 8.5 N0.0590 40.73 40.50/38.90 37.77 42.50/0 7 N0.0595 40.17 40.60/38.70 38.98 41.40/34.80 7 N0.05100 39.85 40.70/38.50 38.90 41.30/34.50 9.5 N0.05110 39.80 40.50/38.00 37.30 30.40/39.30 4 N0.05115 39.77 41.20/37.00 37.60 40.50/31.90 5.5 N0.05120 39.47 40.50/38.00 38.16 40.20/32.40 8 N0.05

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illustrated in the Tables 2 to 6 no significant differences were found inP80-AEP and N120-AEP amplitude and latency between the shamand NVHL rats. However, as showed in Table 1, we found significantdifferences in the N40-AEP amplitude between sham and NVHL rats (*p b 0.05).

3.3. Histological findings on the number of cortical cells in sham versusNVHL rats

We found that rats with NVHL exhibit a significant reduction in thenumber of cortical cells in bilateral regions of the temporal cerebral cortexcompared to sham rats. Fig. 4 illustrates histological pictures of the tem-poral cerebral cortex in both sham and NVHL rats as indicated. Note thereduced number of cells in the image of the NVHL rats. A statistical anal-ysis of the mean number of cells indicates a significant small number ofcells for the NVHL rats compared to the sham rats (p b 0.001, Student’st-test).

In Fig. 5A we illustrate the mean amplitude of the N40-AEP elicitedat 120 dB (i.e., the maximal N40-AEP amplitude recorded in 5 NVHLand 4 sham rats) versus the mean number of cells found in the samerats employed in the AEP study (blue circles represent values obtained

Table 1The median, maximums and minimums of the N40-AEP amplitude for sham and NHVLrats. Mann–Whitney U test statistics values are shown for sham group versus NVHL groupamplitude differences. The asterisks indicate statistically significant differences betweenmedians for sham versus NVHL rats.

Stimulus Intensity(dB)

Sham NVHL U P

Median(μV)

Max/min(μV)

Median(μV)

Max/min(μV)

80 11.74 16.28/0 5.53 13.74/0 6 N0.0590 24.92 29.05/22.80 9.31 18.30/0 0 b0.05*95 28.39 24.50/39.59 14.27 24.48/13.52 2 b0.05*100 30.96 39.59/24.50 18.52 26.55/13.52 1 b0.05*110 34.80 40.50/32.48 23.22 30.81/18.19 0 b0.05*115 40.96 45.12/38.09 23.17 33.63/18.13 0 b0.05*120 42.44 40.14/46.00 22.99 36.96/15.54 0 b0.05*

Please cite this article as: Romero-Pimentel, A.L., et al., Histological correlathippocampal lesion: animal model of..., Schizophr. Res. (2014), http://dx.d

from NVHL rats and red circles from sham rats). We obtained a signifi-cant Pearson’s correlation coefficient of r = 0.67 with a p = 0.04, and7 degrees of freedom. Fig. 5B shows the mean values of the N40-AEPamplitude and the corresponding mean number of cells in both groupsof rats (NVHL: blue circle, and sham: red circle).

4. Discussion

We found that adult rats with a NVHL exhibit a significant reductionboth in the amplitude of the N40-AEP component as well as in the den-sity of cells in the temporal cerebral cortex. Thesefindings suggest a cor-relate between the decrease in the amplitude of the N40-AEP and thedensity of neurons in the temporal lobe of NVHL rats. Our electrophys-iological findings parallel those from patients with schizophrenia, inwhich decreases in N100 amplitude have been reported (Turetskyet al., 2009; Light et al., 2012). These findings are compelling becausethere are intriguing reports in the literature about an anatomic-physiological correlate in schizophrenic patients in which a reductionin the amplitude of the P300 response is correlated with a reductionin the volume of the left posterior superior temporal gyrus (McCarleyet al., 1993; 2002), the anterior medial temporal cortex (Kawasakiet al., 1997) and the anterior cingulate cortex (Preuss et al., 2010). How-ever, there are studies that contradict these findings, showing that cor-relations between volumes of temporal lobe structures and left P300amplitudes are low and not significant (Havermans et al., 1999;Meisenzahl et al., 2004). Our findings provide support to the studiesby Light et al. (2012), Turetsky et al. (2009), McCarley et al. (1993,2002)) Kawasaki et al., (1997) and Preuss et al., (2010).

Another consistent electrophysiological abnormality in schizo-phrenic patients is the deficit in sensory gating as measured by theP50 conditioning-testing paradigm, in which two brief auditory stimuli(usually clicks) are presented in rapid succession, typically 500 msapart. These paired stimuli are presented typically at 10-sec intervals.The amplitude of the P50 response to the second stimulus (S2) in nor-mal subjects is typically attenuated compared to the response to the

Table 3The median, maximums and minimums of the P80-AEP amplitude for sham and NHVLgroups. Mann–Whitney U test statistics values are shown for sham group versus NVHLgroup amplitude differences.

Stimulus Intensity(dB)

Sham NVHL U P

Median(μV)

Max/min(μV)

Median(μV)

Max/min(μV)

80 0 13.08/0 2.06 12.16/0 10 N0.0590 3.54 19.92/0 5.34 12.97/0 11.5 N0.0595 11.99 20.45/5.21 6.57 14.18/0.79 6 N0.05100 11.61 22.57/3.39 8.74 16.68/7.23 11 N0.05110 12.88 21.42/9.14 7.39 11.28/4.07 3 N0.05115 14.72 32.20/10.71 4.46 12.30/2.38 2 N0.05120 16.33 35.22/11.00 8.50 11.91/7.64 1 N0.05

es of N40 auditory evoked potentials in adult rats after neonatal ventraloi.org/10.1016/j.schres.2014.09.009

Table 4Themedian,maximums andminimums of the P80-AEP latency for sham andNHVL group.Mann–Whitney U test statistics values are shown for sham group versus NVHL group la-tency differences.

Stimulus Intensity(dB)

Sham NVHL U P

Median(ms)

Max/min(ms)

Median(ms)

Max/min(ms)

80 38.80 84.30/0 0.00 92.30/0 10 N0.0590 75.10 108.90/0 86.95 90.70/0 9.5 N0.0595 76.65 78.60/68.30 77.50 90.00/70.00 8 N0.05100 79.40 86.10/77.30 76.70 99.70/70.10 10 N0.05110 76.00 81.30/67.9 82.30 102.30/70.00 7 N0.05115 76.10 82.20/70.00 87.95 99.70/69.00 6 N0.05120 73.05 76.00/69.20 87.15 98.45/72.90 4 N0.05

Table 6The median, maximums and minimums of the P120-AEP latency for sham and NHVLgroup. Mann–Whitney U test statistics values are shown for Sham group versus NVHLgroup latency differences.

StimulusIntensity (dB)

Sham NVHL U P

Median(ms)

Max/min(ms)

Median(ms)

Max/min(ms)

80 0 137.70/0 0 150.70/0 11 N0.0590 0 149.00/0 145.15 160.80/0 4.5 N0.0595 148.50 160.00/0 146.85 158.98/124.20 10.5 N0.05100 140.05 147.00/125.40 145.50 174.20/127.80 7 N0.05110 144.00 150.00/104.20 132.00 163.80/118.00 8 N0.05115 145.00 162.50/123.20 147.80 163.80/127.00 10 N0.05120 148.85 160.80/121.50 148.00 160.00/123.00 11 N0.05

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first stimulus (S1), due to inhibitory effects associatedwith the responseto S1. The magnitude of this inhibitory effect is referred to as P50 sup-pression, or P50 sensory gating, and is reduced in schizophrenic sub-jects. Independent groups have been able to replicate this basic P50sensory gating deficit in schizophrenia. Similarly, deficits in sensory gat-ing and reduced paired pulse inhibition (PPI) of startle have been de-scribed in NVHL rats (Vohs et al., 2009; Swerdlow et al., 2012). Thepresent results further characterize auditory processing deficits in thecontext of the N40-AEP of NVHL rats and suggest a possible neuroana-tomical correlate of these deficits: the reduced density of cells in thetemporal cortex.

Moreover, it could be plausible that a reduction in cells in the tempo-ral cortex is associatedwith a reduction of inhibitory neurons at the cor-tical level and at the first stages of the sensory processing; which isconsistent with recent studies by Macedo et al. (2010) who observedan enhancement of AEPs in the inferior colliculus of NVHL rats, andChambers et al. (1996) and Swerdlow et al. (2001), whoobserved an as-sociated gliosis and calcification in the lateral thalamus, thus suggestingthat these NVHL rats have alterations in themechanisms of inhibition inearly phases of the acoustic processing.

It is important to mention that the group sizes of NVHL (n= 5) andsham (n = 4) were determined according to the following practical,ethical and experimental considerations: 1) the care of these animalswith a brain lesion is a demanding task, because the experimentermust take strict care of the animals since the day of the neonatal lesionto the adulthood, 2) the Mexican guidelines for the care and use of lab-oratory animals recommends to reduce the number of animals for ex-perimentation, 3) all animals that were employed were obtained fromdifferent litters of rats; thus indicating that they represent a fair sampleof this NVHL animal model. 4) the analysis of our experimental datawith this sample size is sufficient to observe statistically significant dif-ferences (p b 0.001 and p b 0.05).

In humans and rats the acoustic information processing begins in thecochlea and is sent to the cochlear nuclei and to the superior olivarycomplex, either on the same side or opposite side. Then, the informationtravels from the superior olivary complex, either on the same side or

Table 5The median, maximums and minimums of the P120-AEP amplitude for sham and NHVLgroup. Mann–Whitney U test statistics values are shown for sham group versus NVHLgroup amplitude differences.

Stimulus Intensity (dB) Sham NVHL U P

Median(μV)

Max/min(μV)

Median(μV)

Max/min(μV)

80 3.707 7.80/0 0 2.33/0 8 N0.0590 1.189 2.40/0 1.869 8.45/0 7 N0.0595 4.150 10.57/0 5.367 11.43/1.43 9 N0.05100 4.075 5.57/1.98 6.69 15.87/3.27 7 N0.05110 2.75 14.12/2.28 9.00 10.72/5.00 8 N0.05115 5.97 6.27/1.31 8.69 15.82/2.17 6 N0.05120 6.30 10.55/3.42 9.13 16.20/3.31 9 N0.05

Please cite this article as: Romero-Pimentel, A.L., et al., Histological correlatehippocampal lesion: animal model of..., Schizophr. Res. (2014), http://dx.d

opposite side, crossing in the trapezoid body and ascending on theother side. They form a tract called the lateral lemniscus, this carriesthe auditory information upward through the pons to the inferiorcolliculus of the midbrain. After this, the information travels to the me-dial geniculate nucleus of the thalamus. The auditory information finallyis projected to the temporal area of the cerebral cortex (Hendelman,2006). Furthermore, the ventral half of the CA1-hippocampus projectslightly to the primary auditory regions of the cerebral cortex(Cenquizca and Swanson, 2007). This auditory network of communica-tion could be affected byNVHL. In histological studies, NVHL rats show athin layer of calcium deposits close to the lesioned area, mainly withinthe auditory thalamus and the zona incerta, in addition to the ventralhippocampus. This abnormality affecting the auditory thalamic regionhad also been indicated by some other authors, described as a “mildgliosis” in lateral thalamic structures adjacent to the hippocampus(Chambers et al., 1996; Swerdlow et al., 2001; Macedo et al., 2010;Sandner et al., 2010). There are at least three possible causes for thesehistological findings. First, at the time of the lesion (7 days postnatal),and close to the injection site, a layer of migrating neurons very sensi-tive to ibotenate could be destroyed, and the resulting sclerotic layercould be calcified (Beas-Zárate et al., 2001). Second, the calcificationcould be the consequence of glial damage, because some microglialcells have high sensitivity to NMDA agonist during the neonatal period(Tahraoui et al., 2001). Finally, it could be consistent with a calcificatedhematoma that could occur subsequently to the destruction of the en-dothelium of the anterior choroidal artery, which passes throughoutthe lesioned area (Scremin, 1995).Whatever the cause, these histopath-ological changes might lead to inappropriate innervation within thethalamic-cortical pathways.

Destroying the ventral hippocampus could deprive some importanthippocampal afferents as well. These areas could be atrophied becauseof the loss of a neurotrophic influence mediated by hippocampal affer-ent axons. Reports in the literature of a reduced number of neurons inthe cortex of NVHL rats support this possibility (Halim and Swerdlow,2000; Flores et al., 2005; Tseng et al., 2008 and Francois et al., 2009). Adeficit in dendritic complexity after NVHL must also be considered(Chambers et al., 2010). This atrophy could be determined by the lossof the neurotrophic effect of glutamate, since the neuronal outputs ofthe ventral hippocampus are primarily glutamatergic (Bardgett andHenry, 1999). For example, a trophic influence has been documentedfor glutamate in the auditory system. Thus, glutamate that is releasedwhen the afferent fibers are active may be necessary to sustain the an-atomical structure of the target brain areas (Hyson, 1997).

In conclusion, the present results indicate that the NVHL ratmodel for schizophrenia replicates a robust electrophysiologicalendophenotype for schizophrenia, of decreased amplitude of theP50 and N100 auditory evoked potential (see Fig. 1 from Rosburget al., 2008 and compare such figure with our Figs. 1 and 2). More-over, this alteration in auditory evoked potentials in NVHL rats is as-sociated with a significant decrease in cell number in the temporalcortex. The present results represent an important step in identifying

s of N40 auditory evoked potentials in adult rats after neonatal ventraloi.org/10.1016/j.schres.2014.09.009

Fig. 4. A) Histological pictures of sections of the auditory temporal cortex in sham versus NVHL rats as indicated. B) Comparison between the estimated numbers of cells in both hemi-spheres relative to the thickness in sham versus NVHL rats. C) The same as B, but for the right auditory temporal cortex. D) The same as B, but for the left auditory temporal cortex. Sta-tistical analyses indicate significantly fewer cells for the NVHL rats compared to the sham rats (** p b 0.001, *p b 0.05).

6 A.L. Romero-Pimentel et al. / Schizophrenia Research xxx (2014) xxx–xxx

possible neuroanatomical and neurophysiological bases for the sub-tle but significant deficits in the primary sensory processing of audi-tory stimuli in schizophrenia.

Role of the funding sourceThe electrophysiological devices and other instruments employed in the experiments

were acquired with funds from the following grants: CONACYT F1-153583 (EM) and138663 (GF) and CátedraMarcosMoshinsky (EM). RPAL acknowledge fellowship supportfrom CONACyT Mexico.

Author contributionsRomero-Pimentel AL, Hoffman KL, Flores G andManjarrez E, designed the experiment

and methods. Romero-Pimentel AL, Vázquez-Roque RA, Camacho-Abrego I, Hoffman KL,

Fig. 5. A)Mean amplitude of N40-AEP elicited by auditory stimuli at 120 dB versus themean nucircles) and sham rats (red circles).We found a statistically significant Pearson’s correlation coefthe pooled data illustrated in panel (A); the blue circle is for NVHL rats and the red circle for shadecreased N40-AEP mean amplitude (* p b 0.05) for the NVHL rats compared to the sham rats

Please cite this article as: Romero-Pimentel, A.L., et al., Histological correlathippocampal lesion: animal model of..., Schizophr. Res. (2014), http://dx.d

Linares P, Flores G, Manjarrez E carried out the experiments and analyzed data. Romero-Pimentel AL, Hoffman KL, Flores G, Manjarrez E interpreted data and wrote the manu-script. All authors approved the manuscript.

Conflict of interestThe authors declare that the research was conducted in the absence of any commer-

cial or financial relationships that could be constructed as a potential conflict of interest.

AcknowledgementsThis work was supported by the following grants: CONACyT under projects: F1-

153583 (EM) and 138663 (GF), VIEP-BUAP-00070, PIFI-2008-BUAP and Cátedra MarcosMoshinsky (EM), Mexico. RPAL acknowledge fellowship support from CONACyT Mexico.

mber of cells found in both hemispheres of the auditory temporal cortex inNVHL rats (blueficient of r=0.67with a p= 0.04, and 7 degrees of freedom (gray line).B)Mean values ofm rats, respectively. Statistical analyses indicate significantly fewer cells (* p b 0.001) and a.

es of N40 auditory evoked potentials in adult rats after neonatal ventraloi.org/10.1016/j.schres.2014.09.009

7A.L. Romero-Pimentel et al. / Schizophrenia Research xxx (2014) xxx–xxx

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