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Neonatal ventral hippocampal lesions modify pain perception and evoked potentials in rats
Behavioural Brain Research 234 (2012) 167–174
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Neonatal ventral hippocampal lesions modify pain perception and evoked potentials in rats Guy Sandner a,∗ , Laurence Meyer b , Marie-Josée Angst a , Blandine Guignard c , Thierry Guiberteau c , Ayikoe Guy Mensah-Nyagan b a
U666 INSERM, Institut de Physiologie, Faculté de Médecine, Université de Strasbourg, Strasbourg, France Equipe Stéroïdes, Neuromodulateurs et Neuropathologies, EA-4438, Université de Strasbourg, Strasbourg, France c UMR 7191 CNRS/UdS, Faculté de Médecine, Université de Strasbourg, Strasbourg, France b
h i g h l i g h t s
Neonatal ventral hippocampal lesions (NVHL) elicit mechanical hypoalgesia. NVHL elicit thermal hyperalgesia. NVHL enhance the threshold of cortical auditory evoked potentials. NVHL suppress the sensory gating effect assessed by auditory evoked potentials. NVHL did neither modify visual nor tactile cortical evoked potentials.
a r t i c l e
i n f o
Article history: Received 3 May 2012 Received in revised form 20 June 2012 Accepted 22 June 2012 Available online 3 July 2012 Keywords: Audition Vision Tactile Sensory gating Schizophrenia
a b s t r a c t This work concerns the debate surrounding the modified pain reactivity of patients with schizophrenia and other possible perceptive distortions. Rats with a neonatal ventral hippocampal lesion (NVHL) were used to model the neuro-developmental aspect of schizophrenia, and their reactivity to various stimuli was evaluated. The results could also help understand sensory deficits in other neuro-developmental disorders. Behavioural reactions to graduated painful thermal and mechanical stimuli were observed, and evoked potential responsiveness to tactile, visual and acoustic non-painful stimuli was recorded and compared to non-operated and sham lesioned controls. A higher threshold was observed with painful mechanical stimuli and shorter paw withdrawal latency with thermal stimuli. This was particularly relevant as there was no change in the evoked potentials triggered by non-nociceptive tactile stimulation of the same part of the body. There was a 10 dB(A) increase in the auditory threshold and a suppression of auditory sensory motor gating. Visually evoked potentials did not appear to be affected. Taken together, the results showed that NVHL-evoked alteration of brain development induces mechanical hypoalgesia, thermal hyperalgesia and auditory sensory changes. The data also contribute towards elucidating mechanisms underlying sensory deficits in neurodevelopmental diseases, including schizophrenia. © 2012 Elsevier B.V. All rights reserved.
1. Introduction As suggested by epidemiological studies, schizophrenia is a neuro-developmental disorder originating in the pre-natal period of life [1–4]. It manifests itself in young adults via symptoms, cognitive perturbations such as attention and memory impairments, and alterations of sensory-motor capacities [5–7]. Lower animal models aimed at understanding symptoms are beset by the
∗ Corresponding author at: Faculté de Médecine, Université de Strasbourg, 11 rue Humann, 67085 Strasbourg, France. Tel.: +33 3 688 53 255; fax: +33 3 688 53 256. E-mail address: [email protected] (G. Sandner). 0166-4328/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.bbr.2012.06.026
impossibility of identifying positive symptoms, such as delusions or auditory verbal hallucinations. Interpreting data from studies on human attention and memory remains difficult because the theoretical framework of most human cognitive studies cannot be directly transposed to lower animals. For instance, theories such as the one developed by Posner [8] about human attention using arrows to guide spatial attention in a visual scene or by Baddeley [9], who considers that working memory involves a verbal and spatio-temporal loop co-administered by a central executive system, describe complex brain functions not easily tested in lower animals although considered essential for understanding patients’ deficit [10,11]. More objectively measurable features of schizophrenia, such as minor abnormalities in sensorimotor processes, can be
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more readily addressed in lower animal studies. Sensory deficits have been evidenced in patients using psychophysical methods, evoked potential recordings, and functional brain imaging [12], especially with regard to painful stimuli [13,14]. Some of these methods can be used in lower animals. Neonatal ventral hippocampus lesions (NVHL) in rats produce an animal model commonly used to document the neurodevelopmental aspect of schizophrenia (review in [15–17]). It consists in causing ventral hippocampal damage at the end of the first week of life. With the help of MRI imaging methods [18–21] the damage can be visualized two weeks later. Even if no such lesions exist in patients with schizophrenia, they seem to modify brain development in a similar way, which is now considered crucial for the construct validity of the model [17,22]. Frontal and cortical-striatal dysfunction is expressed as a syndrome encompassing certain symptom components as well as cognitive deficits plus addiction vulnerability, rather similar to what was observed in schizophrenia (even if the direct human-low animal comparison remains beset with the aforementioned theoretical and practical difficulties). That the behaviour of NVHL rats could be shaped by environmental conditions throughout adolescence also raised the question of the part played by the sensory systems in the disorders observed in adult animals. This provided ample justification for a systematic investigation of the sensory capacity of NVHL rats. In the present study, experimenters familiar with studies on lower animal pain used standard methods [23–26] to compare the reactivity of NVHL rats to heat and mechanical pain with that of sham-lesioned controls and non-operated rats. Afterwards, chronic recording electrodes were inserted into the primary auditory, visual and somato-sensory cortices to record auditory, visual and tactile evoked potentials in these NVHL rats and their shamlesioned controls, again by means of standard procedures [27–30]. Fitted with an auditory cortex recording electrodes, the rats were also subjected to two consecutive acoustic pulses to test the sensory gating effect which appeared to be reduced in several other models and in the disease [29–33]. 2. Materials and methods The methodology and protocols were approved by the French Regional Ethics Committee of Alsace (CREMEAS) under the reference AL/02/02/02/10. All the procedures were conducted in compliance with French legislation and EU Directive 2010/63/EU for animal experiments.
2.3. Selecting subjects using magnetic resonance imaging Twenty-one-day-old lesioned pups were subjected to an MRI session under isoflurane anaesthesia. MRI was performed on a small-animal scanner operating at 4.7 T (TR/TE/TEeff: 3000/30 ms/60 ms). A series of 10 slices (512 × 512 pixels) was generated over a 1 cm long section of the brain, rostral to the cerebellum–cerebrum gap, as in our previous studies and those conducted by others [18–21,34,35], the purpose being to select a set of homogeneous bilaterally lesioned rats for the behavioural tests. The present study included nine rats with a moderate bilateral lesion similar to the lesions shown by Al Amin et al. [36]. They were compared to 9 sham-lesioned and 9 naïve rats for nociception. 2.4. Reactions to thermal and mechanical stimuli applied to the hind paws The rats were first tested for their reaction to increasing thermal stimuli (plantar test) and mechanical (von Frey test) stimuli in a random sequence. 2.4.1. Plantar test Reactions to thermal stimuli were assessed with a Plantar Test Apparatus (Ugo Basile, Comerio, Italy) which measured paw withdrawal latency in response to radiant heat. Each rat was placed individually in a clear Plexiglas box (23 cm × 18 cm × 14 cm) positioned on a transparent surface and given 10 min to become accustomed to the apparatus before testing commenced. The heat source was then placed under a hind paw. An infra-red light beam was activated, with this heat source connected to a timer which switched off the heat automatically whenever the paw was withdrawn or after a 20 s cut-off time to prevent tissue damage in the absence of a response. The withdrawal latency of each hind paw was recorded, with the mean hind paw withdrawal latency taken from the average of three separate measurements per paw. The testing box was thoroughly cleaned between test sessions to prevent any effect of olfactory odour stress cues which could have influenced measurements. 2.4.2. von Frey test The mechanical nociceptive sensitivity threshold was evaluated in individual rats placed in Plexiglas boxes (30 cm × 30 cm × 25 cm) on a metal grid that allowed access to the plantar surface of their hind paws. A series of calibrated von Frey hairs (Stoelting, Wood Dale, IL) were applied to the plantar surface of each hind paw with increasing force (1, 2, 4, 6, 8, 10, 15, 26, 60, 100, 180, and 300 g) until the individual filament used just began to bend. The filament was applied for 1–2 s and the procedure repeated 5 times at 4–5 s intervals. The threshold for paw withdrawal was evaluated (in grams). Only robust and immediate withdrawal responses followed by paw licking were considered positive. We already know from previous studies that naive untreated rats never withdraw from stimulations under 6 g but respond 15–20% of the time to a 15 g stimulus and over 70% of the time to a 80 g stimulus which is therefore regarded as an indisputable nociceptive stimulation [23–26]. If they failed to respond to the 300 g von Frey hair, the test result was recorded as 300 g. 2.4.3. Data analysis The measured variables, latency or strength, were subjected to ANOVAs, with paw (left or right) and 3 or 5 tests as within-group variable and treatment (NVHL, sham or non-operated controls) as between-group variable.
2.1. Animals
2.5. Evoked potentials
Four Sprague Dawley dam rats, each with 8 male pups, were purchased from Charles River (France), and housed on a 14/10-h light/dark cycle (lights on at 7 AM) with food and water provided ad libitum. When 7 days old, the pups were subjected to a lesion or sham lesion. MRI pictures obtained when the lesioned pups were 3 weeks old were used to select those with bilateral lesions relevant for the experiments (see Fig. 1). Behavioural tests were conducted in 12–24-week-old adult rats. The rats were then killed, brain sections prepared and histology performed to verify the appearance of the lesion. A group of 9 naïve rats, similar in age and weight to the lesioned and shamlesioned rats and also purchased from Charles River (France), were included in the study to ensure the methodology used to test the painful thresholds yielded similar responses in the sham and naïve control groups as in the naïve control group and controls from previous experiments [23–26].
We assessed brain reactions to non-painful acoustic, visual and tactile stimuli by recording cortical evoked potentials in freely moving rats. Recordings were obtained from intracranial electrodes implanted during a second surgical procedure under anaesthesia (ketamine, i.m., 100 mg/kg, and xylazine, i.m., 10 mg/kg). Since the electrodes were used for a long time, we waited until the rats were 4 months old, i.e. until their skull size was relatively stable. The experiments were spread over a 2-month period because the rats had to be handled individually for the evoked potential recording session. The methods used in the present study were transposed from those reported in the literature [27,28,33,37].
2.2. Post-natal surgery Surgical procedures were carried out 7 days after birth under isoflurane anaesthesia as detailed previously [18–20,34,35]. Either 0.3 L of ibotenic acid (Sigma, France, 10 g/L, pH 7.4), in the case of NVHL rats (N = 23), or artificial cerebrospinal fluid, in the case of sham-lesioned rats (N = 9), was infused bilaterally into the ventral hippocampus. Three weeks after surgery, the pups were weaned and housed two per cage.
2.5.1. Implanting the recording electrodes Three stainless steel enamel electrodes (OD: 0.25 mm) were implanted in the left cortex and aimed at the primary visual, sensory and auditory cortices, respectively. The coordinates relative to the bregma were: visual cortex, 3 mm lateral, 9 mm caudal and 3 mm ventral; somatosensory cortex, 2 mm lateral, 1.5 mm caudal and 2 mm ventral; auditory cortex: 6 mm lateral, 6 mm caudal and 5 mm ventral with a 20◦ medio-lateral angle. The enamel was removed from the bottom 0.5 mm of the intracranial recording electrode tip. The other tip of the electrode was connected to a micro-connector pin. One of the remaining pins was connected to a screw placed in the frontal bone and acted as the earth. Another pin was connected to a screw placed equidistant from the 3 electrodes and served as the voltage reference electrode. The electrodes, micro-connector and screws were sealed with dental cement.
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Fig. 1. Aspect of the lesions according to RMI. Upper pictures: MRI of a typical lesion. The arrows point to the lesioned part of the ventral hippocampus. Lower drawings: Minimum and maximum extent of the lesions considered for the purpose of the experiments. In the upper and lower drawings, coronal sections were adapted from those of Paxinos and Watson [74]. The distance from Bregma is indicated under each section. Abbreviations: fr: fasciculus retroflexus; ml: medial lemniscus; mp: mammillary peduncle; PAG: periaqueductal grey; SN: substantia nigra.
2.5.2. Evoked potential recording sessions A computer triggered light produced by a series of high-intensity white light emitting diodes (onset latencies in the s range), a white noise generator connected to a loudspeaker at the bottom of the test cage (onset latency in the ms range), or an electromagnet fixed vertically to a platform on which the rat was standing (onset latency in the ms range). Each of these stimulating devices was placed in a specific test cage. The three test cages were all the same size (vertical cylinder 40 cm high and 20 cm in diameter). The visual stimulation test cage was surrounded by a sheet of light-reflective aluminium paper. The bottom of the auditory stimulation test cage was a grid separating the rat from the membrane of the loudspeaker. The bottom of the tactile stimulation cage was made from a disc of Plexiglas held in place by 4 springs. The middle of it was connected to the core of the electromagnet. The stimulus-delivering interface was calibrated to deliver stimuli of 5 different strengths, as follows: light measured at the usual place of a rat’s eyes → 400, 150, 30, 10, 3 cd/m2 ; sound measured at the usual place of a rat’s ears → 105, 95, 85, 75, 65 dB(A); pressure of the moving platform → 3100, 1500, 600, 200, 100 N/m2 . The response of each brain site was assessed for the 5 stimulus strengths in random sequence. The brain electrodes were connected to an amplifier (PsyLab, Gain ×20 000, bandwidth: 0.1–40 Hz), the two channels of which were connected to the relevant electrode and to one of the other electrodes so that two evoked responses were recorded at once, the targeted response and another one as a control for the purpose of checking the topographical specificity of the evoked response. An evoked potential was obtained only with the relevant electrode except when the auditory cortex was considered and a tactile stimulus applied (NB, the movement of the device delivering the tactile stimulus was somewhat noisy). The amplifier outputs were connected to a 12-bit analogue–digital converter. A digital output channel of this interface was used to trigger visual, auditory or tactile stimuli depending on the electrode selected. This was controlled by a home-made LabView (National Instruments) program, which delivered 50 stimuli, each lasting 400 ms, with one every 3–5 s (randomized intervals), and recorded the subsequent evoked potential for a period of 125 ms (measurement frequency = 1000 Hz). The recordings were examined and added up, except in the case of saturation (less then 5% of cases). The resulting mean evoked potential was stored for further analyses. 2.5.3. Data analyses The latency (from the onset of the stimulus to the beginning of the evoked response (P1 wave) and amplitude (maximum evoked P1–N1 potential change) were measured for each electrode and each level of stimulus. The relationship
between the amplitude of the evoked potential response and strength of the stimulus was drawn on a graph. The stimulus threshold and slope of the transfer function, representing the sensitivity of the sensory system considered, were determined directly from the graph (in exactly the same way as in [38]). These parameters were subjected to t-tests (StatView software), with lesion status as the controlled variable (NVHL versus sham-lesioned). 2.5.4. Sensory gating experiment In a final experiment, two 80 dB(A), 1 ms pulses were interspaced by a 100 ms interval. The two subsequent evoked potentials were recorded and compared. Since the variances were correlated with the amplitudes, they were not directly suitable for an ANOVA. However, an ANOVA was performed on the logarithm of the amplitudes, with the two consecutive evoked potentials as within-group variable and lesion status as between-group controlled variable. We also submitted the means of individual differences to a t-test.
3. Results 3.1. Reaction to thermal and mechanical stimuli applied to the hind paws 3.1.1. Plantar test The lesion had a significant effect on withdrawal latency (F(2,24) = 36.54, p < 0.0001) with no difference between paws (F(1,24) = 0.97). The testing sequence yielded a significant effect (F(2,48) = 5.62, p < 0.01), but its interaction with the lesion was not significant (F(4,48) = 2.5). Mean latencies with the testing series also revealed a significant effect of lesion (F(2,24) = 36.53, p < 0.0001), due to a difference between NVHL and sham-lesioned rats (p < 0.0001) as well as between NVHL and non-operated controls (p < 0.0001), but not between sham-lesioned rats and nonoperated controls (p 0.99). As the bar graph to the left of Fig. 2 shows, withdrawal latency was shorter in NVHL rats, an indication of hyperreactivity to thermal stimulation.
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withdrawal response could be elicited in NVHL rats, an indication of hyposensitivity to mechanical pain. 3.2. Evoked potentials 3.2.1. Single auditory stimuli Fig. 3 illustrates the method used to analyze the evoked potentials on a representative result obtained with a sham-lesioned rat. The upper graph series are the mean evoked potentials as recorded in the auditory cortex (through the filter of the EEG recording system). The amplitudes appeared as a linear function of the stimulus strength (expressed in dB, the actual relationship being logarithmic). In this example of a typical “throughput” relationship the threshold was about 60 dB(A) (the mean threshold in sham-lesioned rats was 64 dB(A)). The thresholds for all rats that provided valid throughput functions (NVHL N = 8, Sham N = 8) differed between the NVHL and sham-lesioned rats (t = −2.32, p < 0.05), as illustrated at the bottom right of Fig. 3, the NVHL being 10 dB(A) less sensitive to the noises. Neither the slope of the throughput function (t = −0.86), nor latency (t = 1.9) differed. The mean latency was 8 ms. Fig. 2. Responses to painful stimuli. Bars in the left bar graph denote means (+SEM) of the latency to withdraw the hind paw in the plantar test (in seconds). Bars of the right bar graph denote means (+SEM) of the force that has to be applied to the plantar part of the hind paw with a von Frey hair to trigger its withdrawal. NVHL rats were compared to both sham lesioned rats and non-operated controls (***p < 0.001).
3.1.2. von Frey test The lesion had a significant effect on the strength of the stimulus that had to be applied before eliciting a withdrawal reaction (F(2,24) = 18.27, p < 0.0001). There was no difference between paws (F(1,24) = 3.52), and the test sequence was not significant (F(4,96) = 0.18). The lesion had a significant effect on mean strength (F(2,24) = 18.27, p < 0.0001), due to a difference between NVHL and sham-lesioned rats (p < 0.001) as well as between NVHL and nonoperated controls (p < 0.0001), but not between sham-lesioned rats and non-operated controls (p 0.46). As shown in the bar graph to the right of Fig. 2, a harder von Frey hair had to be used before a
3.2.2. Single visual stimuli In the cases that provided an acceptable throughput function when the response to light was tested (NVHL N = 6, Sham N = 7), there was no difference between the NVHL and sham-lesioned rats in terms of threshold (t = 0.56), sensitivity (t = 0.56), or latency (T = −0.07). The mean latency was 27 ms. 3.2.3. Single tactile stimuli In the cases that provided an acceptable throughput function when the response to a tactile stimulus was tested (NVHL N = 9, Sham N = 8), there was no difference between the NVHL and shamlesioned rats in terms of threshold (t = 0.70), sensitivity (t = 1.04), or latency (T = −1.10). The mean latency was 16 ms. 3.2.4. Sensory gating experiment As indicated in the previous section on auditory evoked potentials, 8 NVHL and 8 sham rats were used. There was a significant
Fig. 3. Auditory evoked potentials. The 5 upper graphs correspond to an example of evoked potentials in microvolt in a control rat, the y axis being the same for all graphs. The x axis is the time elapsed after application of the stimulus. Each evoked potential was triggered by a sound the loudness of which is indicated in dB(A) to the top right of each graph. The dotted line signals the beginning of the response. P1 and N1 were the waves considered in this study. The amplitude of the response corresponds to the P1–N1 difference as indicated by the vertical line with arrows. Amplitudes were plotted as a function of the loudness of the sound below to the left. The mean intercepts (+SEM) of this relationship with the x axis, i.e. the evoked potential threshold, for all rats considered are plotted on a bar graph to the bottom right.
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Fig. 4. Sensory gating. The mean evoked potentials (+ or − SEM) obtained after a first sound (1) and after a second sound occurring 100 ms later (2) are represented as the left hand bar graph for sham-lesioned and NVHL rats. The grey arrow shows the sensory gating effect of sham-lesioned rats. The right hand bar graph illustrates the means of the individual 1 → 2 differences for sham-lesioned and NVHL rats.
interaction between the lesion and two successive responses (F(1,16) = 5.19, p < 0.05). With respect to the individual ratios, i.e. where each subject was its own reference, and when these ratios were compared in a t-test for NVHL and sham-lesioned rats, the result was also a significant difference (t = 2.28, p < 0.05). The ANOVA showed no overall difference between either NVHL and sham-lesioned rats (F(1,16) = 0.33), or the responses to the first and second acoustic pulse (F(1,16) = 0.67), which is understandable given the data shown in Fig. 4. The bar graph on the left hand side shows the usual drop in the response between the first and second stimulus in sham-lesioned rats, a drop not seen in NVHL rats, whose response remained low in keeping with their lower reactivity to acoustic stimuli The ratios represented on the right hand side depict the mean individual differences and show that, contrary to the standard reduction in control rats from one stimulus to the next, in NVHL rats the response even tended to increase. 3.3. RMI and histological observations The lesions were the same size as those considered in our previous studies and correspond to the description given in Al Amin et al.’s [36] report. 4. Discussion 4.1. Reaction to painful stimuli in lower animal models of schizophrenia Modified responsiveness to painful stimuli in lower animal models of schizophrenia has been regularly reported, but the modification has varied according to (i) the model, (ii) type of pain considered, and (iii) evaluation method used. Thermal hyperalgesia has already been reported in NVHL rats, in a study that used the same lesion sizes and evaluation methods as the present study [36], but their reactivity to painful mechanical stimuli remained unaltered. The rats, it is worth noting, were handheld, paw pinches were used rather than calibrated stimuli, and the focus was on withdrawal latency rather than pain threshold, but the fact remains that both studies point to a differential reactivity to thermal versus mechanical pain. Such differential responsiveness to distinct types of pain has seldom been reported. Nevertheless, recent observations pointed to dissociations, such as hyporeactivity to cold painful stimuli (tested by topical application of menthol) but no change in reactivity to mechanical painful stimuli [39], and the abolition of thermal pain and reduced reactivity to noxious
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mechanical stimuli without any change in the reactivity to hot or cold pain [40], this change ensuing from genetic modification of pain detecting neurons. Such examples indicate that the three pain types may work independently of each other in natural living conditions. But an alternative explanation for the dissociation we observed must be considered. A withdrawal reaction to heat is no more than a reflex organized at the level of the spinal chord, whereas the complex behavioural expression of unpleasantness triggered by painful mechanical stimuli requires a higher level of organization. Many other lower animal modelling strategies have been used in studies on schizophrenia, involving submitting animals to social deprivation, modifying their genome, or administering psychoactive drugs (review in: [41]). Social deprivation in the peripubertal period produced hyperalgesia [42,43], as did deleting the “schizophrenia-associated gene”, COMT, or the STOP cytoskeleton gene [44]. Deleting other “schizophrenia-associated genes”, such as NRG1 and DISC1, resulted on the contrary in hypoalgesia [45]. Psychoactive drugs, for instance indirect dopamine agonists or NMDA receptor antagonists, elicited hypoalgesia [46–49]. Insofar as NMDA antagonists are anaesthetics, this was hardly surprising. What common neurobiological substrate would be compatible with the diversity of this modified reactivity to pain? Experiments focusing on the role of the dopaminergic mesocorticolimbic system in the reaction to pain have provided interesting data in this respect. Amphetamine-induced hypoalgesia in rats turned into hyperalgesia after 6-hydroxydopamine lesions were performed in the ventral tegmental area [46], an indication that the functional status of the mesocorticolimbic dopaminergic system, which is dysfunctional in patients, could tip the scale of nociception. 4.2. Pain perception in patients with schizophrenia There are three lines of argument that support the occurrence of hypoalgesia in schizophrenia: (i) clinical case reports, according to which some patients feel little or no pain [50–52], (ii) population-based studies indicating a low prevalence of schizophrenia diagnosis in pain patients [51,53,54], and (iii) experimental studies showing increased pain thresholds in patients [13,14]. Moreover, according to a recent meta-analysis hypoalgesia is one of several manifestations of blunted responses to primary bodily sensations in these patients [13]. Recent studies, including functional imaging methods, have shown that pain tolerance to heat was slightly higher in patients (1.3 ◦ C), with no difference between them and controls as regards either their perception of pain intensity or unpleasantness [14]. In summary, only moderate changes in perception thresholds were observed in patients, in contrast to the occasionally dramatic insensitivity to pain reported in published “case reports” [51,54]. How can a minor sensory deficit become a total sensory neglect? If we assume that the reduced sensitivity to pain reflected enhanced basal hyperactivity of the internal antinociceptive system, it is easy to accept that any situation which triggers an internal antinociceptive response, such as stress, would also enhance that response far more in patients than in healthy persons. It would be interesting to test this hypothesis and understand how such peaks of activity are triggered. The mesolimbic dopaminergic system might be involved, as indicated in the previous chapter of this discussion. An experimental approach using lower animal models could be helpful to that end. 4.3. Extension of the observations to other sensory systems It was not only patients’ pain threshold that was higher but also their basic thermal sensation [55,56]. Furthermore, evoked potential studies also produced evidence of hearing and sight
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deficits [12,38,57–62]. Characterizing NVHL rats’ responsiveness to auditory, visual and tactile stimuli was therefore justified. We found a higher threshold only for auditory evoked response. Evoked potential responses to light and tactile stimuli in NVHL rats were unchanged, but these negative results should be seen with caution, because it is possible the evoked potential method is not sensitive enough to cope with these sensory modalities in albino rats. The reduced sensitivity to sounds found in this study would contradict our previously reported facilitation of reactivity to sounds in NVHL rats [20]. However, the behavioural response considered in these previous studies, consisting of compulsive running triggered by very loud noises, was considered to result from attenuated thalamo-collicular top-down control, a thesis which ties in with modified thalamo-cortical systems observed in patients combined with bottom-up information flow attenuation [63,64]. Our findings suggest it would be helpful to test features common to different sensory modalities in patients, for example the threshold when acoustic or visual stimuli become uncomfortable or painful, including in the test conditions where such transitions would be modified, for instance by manipulating their emotional status. We found no change in visual or tactile evoked potentials in NVHL rats. As far as we are aware from the literature, no such research has ever been conducted on lower animal models of schizophrenia. With respect to the tactile modality, modified spatial distribution of evoked potentials has been reported in patients [65,66]. The “cross-talk” we observed between acoustic and tactile evoked potentials, attributed in Section 3 to the noise produced by the tactile stimulation device, could alternatively result from such modified spatial distribution of the evoked potentials. This would warrant better assessment with the help of specific research involving simultaneous recording in numerous brain sites and spatial reconstructions in NVHL rats. 4.4. Sensory gating in models of schizophrenia and in patients Sensory gating attenuation in NVHL rats had already been clearly demonstrated, but relied on a behavioural criterion, the startle reflex (review in: [15,16]). It was also tested more recently using evoked potential by Vohs et al. [32]. Their raw data in table 1 of their publication look like our own, namely the response to the first stimulus was reduced in NVHL rats and, subsequently, the ratio between the response to the first and second stimuli was lower. However, the results obtained by Vohs et al. did not attain statistical significance except when more refined analyses were conducted. Another neuro-developmental model showed exactly the same sensorygating deficit, including the weaker evoked potential observed after the first of the two acoustic pulses [30]. Pharmacological models provide the same picture [30,67,68]. Meta-analyses show that the amplitude of evoked auditory waves was reduced in patients and coupled with impaired sensory-gating, even though not observed in every study [58,69,70]. In addition, Vohs et al. also found an inconstant response latency in NVHL rats (reported as “a lower phase reproducibility”). This means that the individual evoked responses would be more scattered, and, consequently, the summation process used to evaluate the mean amplitudes would inevitably produce a lower amplitude. Vohs et al. suggest this reflects an inability on the part of NVHL rats and patients to desynchronize quickly from external sensory stimulation as a result of minor disturbances in their cortex neuronal networks [32]. 4.5. Are these observation relevant only for schizophrenia? Modified pain sensitivity is one of the manifestations of Rett syndrome, a severe neuro-developmental disorder [71]. Heightened pain stimuli tolerance was also found in almost 90% cases of children with Phelan-McDermid syndrome, with enhanced
responsiveness to tactile and acoustic stimuli and preserved visual capacities [71]. Insensitivity to pain was found in other disorders, such as a familial dysautonomia, Prader-Willi syndrome and Williams syndrome, together with acoustic hyperreactivity [71]. About 40–70% of children with autism display some abnormality as regards their sensory sensitivity. For them, sudden and unexpected noises can be unbearable. They also often show no reaction to pain and high/low temperatures [72]. This brief review indicates that the same set of sensory modifications was found in several different neuro-developmental diseases, suggesting that our observations with the NVHL model should not be confined to speculations about schizophrenia but could be extended to include other neuro-developmental diseases [73]. 5. Conclusion Animals used as models and patients with schizophrenia, display minor sensory deficits. Convergences between NVHL rats and schizophrenia consisted of attenuated acoustic perception, suppression of sensory-motor gating, and lower reactivity to painful mechanical stimuli. Divergence was confined to enhanced reactivity to heat pain. In general, it reflects a minor but general functional sensory system perturbation. This point of view applies also to the reduced cortical sensory gating phenomenon. Similar perturbations are also found in other developmental diseases. Conflict of interest The authors hereby declare that, other than income received from their main employer, they have received no financial support or compensation from any individual or corporate entity over the past 3 years for research or professional services, and that there are no personal financial holdings that could be perceived as constituting a potential conflict of interest. Financial disclosure This work was funded by INSERM and the University of Strasbourg, France. These institutional funding bodies played no further role in the study design, data collection, analysis, or interpretation, report writing, or decision to submit the paper for publication. Acknowledgements We would like to thank Julien Gobaille and Jacques Knobloch for having looked after the dams and pups so well until they reached adulthood. The RMI images were obtained by courtesy of the Strasbourg Plateforme d’Imagerie in Vivo, LINC, campus médecine, IFR 37 de Neurosciences de Strasbourg. Help with the English language was provided by Mrs Gillian Wakenhut. References [1] Harrison PJ. Schizophrenia: a disorder of neurodevelopment. Current Opinion in Neurobiology 1997;7:285–9. [2] Schultz SK, Andreasen NC. Schizophrenia. Lancet 1999;353:1425–30. [3] Lewis DA, Lieberman JA. Catching up on schizophrenia: natural history and neurobiology. Neuron 2000;28:325–34. [4] Ashe PC, Berry MD, Boulton AA. Schizophrenia, a neurodegenerative disorder with neurodevelopmental antecedents. Progress in NeuroPsychopharmacology and Biological Psychiatry 2001;25:691–707. [5] Mechri A, Bourdel MC, Slama H, Gourion D, Gaha L, Krebs MO. Neurological soft signs in patients with schizophrenia and their unaffected siblings: frequency and correlates in two ethnic and socioeconomic distinct populations. European Archives of Psychiatry and Clinical Neuroscience 2009;259:218–26. [6] Van Os J. Are psychiatric diagnoses of psychosis scientific and useful? The case of schizophrenia. Journal of Mental Health 2010;19:305–17.
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Research report
Neonatal ventral hippocampal lesions modify pain perception and evoked potentials in rats Guy Sandner a,∗ , Laurence Meyer b , Marie-Josée Angst a , Blandine Guignard c , Thierry Guiberteau c , Ayikoe Guy Mensah-Nyagan b a
U666 INSERM, Institut de Physiologie, Faculté de Médecine, Université de Strasbourg, Strasbourg, France Equipe Stéroïdes, Neuromodulateurs et Neuropathologies, EA-4438, Université de Strasbourg, Strasbourg, France c UMR 7191 CNRS/UdS, Faculté de Médecine, Université de Strasbourg, Strasbourg, France b
h i g h l i g h t s
Neonatal ventral hippocampal lesions (NVHL) elicit mechanical hypoalgesia. NVHL elicit thermal hyperalgesia. NVHL enhance the threshold of cortical auditory evoked potentials. NVHL suppress the sensory gating effect assessed by auditory evoked potentials. NVHL did neither modify visual nor tactile cortical evoked potentials.
a r t i c l e
i n f o
Article history: Received 3 May 2012 Received in revised form 20 June 2012 Accepted 22 June 2012 Available online 3 July 2012 Keywords: Audition Vision Tactile Sensory gating Schizophrenia
a b s t r a c t This work concerns the debate surrounding the modified pain reactivity of patients with schizophrenia and other possible perceptive distortions. Rats with a neonatal ventral hippocampal lesion (NVHL) were used to model the neuro-developmental aspect of schizophrenia, and their reactivity to various stimuli was evaluated. The results could also help understand sensory deficits in other neuro-developmental disorders. Behavioural reactions to graduated painful thermal and mechanical stimuli were observed, and evoked potential responsiveness to tactile, visual and acoustic non-painful stimuli was recorded and compared to non-operated and sham lesioned controls. A higher threshold was observed with painful mechanical stimuli and shorter paw withdrawal latency with thermal stimuli. This was particularly relevant as there was no change in the evoked potentials triggered by non-nociceptive tactile stimulation of the same part of the body. There was a 10 dB(A) increase in the auditory threshold and a suppression of auditory sensory motor gating. Visually evoked potentials did not appear to be affected. Taken together, the results showed that NVHL-evoked alteration of brain development induces mechanical hypoalgesia, thermal hyperalgesia and auditory sensory changes. The data also contribute towards elucidating mechanisms underlying sensory deficits in neurodevelopmental diseases, including schizophrenia. © 2012 Elsevier B.V. All rights reserved.
1. Introduction As suggested by epidemiological studies, schizophrenia is a neuro-developmental disorder originating in the pre-natal period of life [1–4]. It manifests itself in young adults via symptoms, cognitive perturbations such as attention and memory impairments, and alterations of sensory-motor capacities [5–7]. Lower animal models aimed at understanding symptoms are beset by the
∗ Corresponding author at: Faculté de Médecine, Université de Strasbourg, 11 rue Humann, 67085 Strasbourg, France. Tel.: +33 3 688 53 255; fax: +33 3 688 53 256. E-mail address: [email protected] (G. Sandner). 0166-4328/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.bbr.2012.06.026
impossibility of identifying positive symptoms, such as delusions or auditory verbal hallucinations. Interpreting data from studies on human attention and memory remains difficult because the theoretical framework of most human cognitive studies cannot be directly transposed to lower animals. For instance, theories such as the one developed by Posner [8] about human attention using arrows to guide spatial attention in a visual scene or by Baddeley [9], who considers that working memory involves a verbal and spatio-temporal loop co-administered by a central executive system, describe complex brain functions not easily tested in lower animals although considered essential for understanding patients’ deficit [10,11]. More objectively measurable features of schizophrenia, such as minor abnormalities in sensorimotor processes, can be
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more readily addressed in lower animal studies. Sensory deficits have been evidenced in patients using psychophysical methods, evoked potential recordings, and functional brain imaging [12], especially with regard to painful stimuli [13,14]. Some of these methods can be used in lower animals. Neonatal ventral hippocampus lesions (NVHL) in rats produce an animal model commonly used to document the neurodevelopmental aspect of schizophrenia (review in [15–17]). It consists in causing ventral hippocampal damage at the end of the first week of life. With the help of MRI imaging methods [18–21] the damage can be visualized two weeks later. Even if no such lesions exist in patients with schizophrenia, they seem to modify brain development in a similar way, which is now considered crucial for the construct validity of the model [17,22]. Frontal and cortical-striatal dysfunction is expressed as a syndrome encompassing certain symptom components as well as cognitive deficits plus addiction vulnerability, rather similar to what was observed in schizophrenia (even if the direct human-low animal comparison remains beset with the aforementioned theoretical and practical difficulties). That the behaviour of NVHL rats could be shaped by environmental conditions throughout adolescence also raised the question of the part played by the sensory systems in the disorders observed in adult animals. This provided ample justification for a systematic investigation of the sensory capacity of NVHL rats. In the present study, experimenters familiar with studies on lower animal pain used standard methods [23–26] to compare the reactivity of NVHL rats to heat and mechanical pain with that of sham-lesioned controls and non-operated rats. Afterwards, chronic recording electrodes were inserted into the primary auditory, visual and somato-sensory cortices to record auditory, visual and tactile evoked potentials in these NVHL rats and their shamlesioned controls, again by means of standard procedures [27–30]. Fitted with an auditory cortex recording electrodes, the rats were also subjected to two consecutive acoustic pulses to test the sensory gating effect which appeared to be reduced in several other models and in the disease [29–33]. 2. Materials and methods The methodology and protocols were approved by the French Regional Ethics Committee of Alsace (CREMEAS) under the reference AL/02/02/02/10. All the procedures were conducted in compliance with French legislation and EU Directive 2010/63/EU for animal experiments.
2.3. Selecting subjects using magnetic resonance imaging Twenty-one-day-old lesioned pups were subjected to an MRI session under isoflurane anaesthesia. MRI was performed on a small-animal scanner operating at 4.7 T (TR/TE/TEeff: 3000/30 ms/60 ms). A series of 10 slices (512 × 512 pixels) was generated over a 1 cm long section of the brain, rostral to the cerebellum–cerebrum gap, as in our previous studies and those conducted by others [18–21,34,35], the purpose being to select a set of homogeneous bilaterally lesioned rats for the behavioural tests. The present study included nine rats with a moderate bilateral lesion similar to the lesions shown by Al Amin et al. [36]. They were compared to 9 sham-lesioned and 9 naïve rats for nociception. 2.4. Reactions to thermal and mechanical stimuli applied to the hind paws The rats were first tested for their reaction to increasing thermal stimuli (plantar test) and mechanical (von Frey test) stimuli in a random sequence. 2.4.1. Plantar test Reactions to thermal stimuli were assessed with a Plantar Test Apparatus (Ugo Basile, Comerio, Italy) which measured paw withdrawal latency in response to radiant heat. Each rat was placed individually in a clear Plexiglas box (23 cm × 18 cm × 14 cm) positioned on a transparent surface and given 10 min to become accustomed to the apparatus before testing commenced. The heat source was then placed under a hind paw. An infra-red light beam was activated, with this heat source connected to a timer which switched off the heat automatically whenever the paw was withdrawn or after a 20 s cut-off time to prevent tissue damage in the absence of a response. The withdrawal latency of each hind paw was recorded, with the mean hind paw withdrawal latency taken from the average of three separate measurements per paw. The testing box was thoroughly cleaned between test sessions to prevent any effect of olfactory odour stress cues which could have influenced measurements. 2.4.2. von Frey test The mechanical nociceptive sensitivity threshold was evaluated in individual rats placed in Plexiglas boxes (30 cm × 30 cm × 25 cm) on a metal grid that allowed access to the plantar surface of their hind paws. A series of calibrated von Frey hairs (Stoelting, Wood Dale, IL) were applied to the plantar surface of each hind paw with increasing force (1, 2, 4, 6, 8, 10, 15, 26, 60, 100, 180, and 300 g) until the individual filament used just began to bend. The filament was applied for 1–2 s and the procedure repeated 5 times at 4–5 s intervals. The threshold for paw withdrawal was evaluated (in grams). Only robust and immediate withdrawal responses followed by paw licking were considered positive. We already know from previous studies that naive untreated rats never withdraw from stimulations under 6 g but respond 15–20% of the time to a 15 g stimulus and over 70% of the time to a 80 g stimulus which is therefore regarded as an indisputable nociceptive stimulation [23–26]. If they failed to respond to the 300 g von Frey hair, the test result was recorded as 300 g. 2.4.3. Data analysis The measured variables, latency or strength, were subjected to ANOVAs, with paw (left or right) and 3 or 5 tests as within-group variable and treatment (NVHL, sham or non-operated controls) as between-group variable.
2.1. Animals
2.5. Evoked potentials
Four Sprague Dawley dam rats, each with 8 male pups, were purchased from Charles River (France), and housed on a 14/10-h light/dark cycle (lights on at 7 AM) with food and water provided ad libitum. When 7 days old, the pups were subjected to a lesion or sham lesion. MRI pictures obtained when the lesioned pups were 3 weeks old were used to select those with bilateral lesions relevant for the experiments (see Fig. 1). Behavioural tests were conducted in 12–24-week-old adult rats. The rats were then killed, brain sections prepared and histology performed to verify the appearance of the lesion. A group of 9 naïve rats, similar in age and weight to the lesioned and shamlesioned rats and also purchased from Charles River (France), were included in the study to ensure the methodology used to test the painful thresholds yielded similar responses in the sham and naïve control groups as in the naïve control group and controls from previous experiments [23–26].
We assessed brain reactions to non-painful acoustic, visual and tactile stimuli by recording cortical evoked potentials in freely moving rats. Recordings were obtained from intracranial electrodes implanted during a second surgical procedure under anaesthesia (ketamine, i.m., 100 mg/kg, and xylazine, i.m., 10 mg/kg). Since the electrodes were used for a long time, we waited until the rats were 4 months old, i.e. until their skull size was relatively stable. The experiments were spread over a 2-month period because the rats had to be handled individually for the evoked potential recording session. The methods used in the present study were transposed from those reported in the literature [27,28,33,37].
2.2. Post-natal surgery Surgical procedures were carried out 7 days after birth under isoflurane anaesthesia as detailed previously [18–20,34,35]. Either 0.3 L of ibotenic acid (Sigma, France, 10 g/L, pH 7.4), in the case of NVHL rats (N = 23), or artificial cerebrospinal fluid, in the case of sham-lesioned rats (N = 9), was infused bilaterally into the ventral hippocampus. Three weeks after surgery, the pups were weaned and housed two per cage.
2.5.1. Implanting the recording electrodes Three stainless steel enamel electrodes (OD: 0.25 mm) were implanted in the left cortex and aimed at the primary visual, sensory and auditory cortices, respectively. The coordinates relative to the bregma were: visual cortex, 3 mm lateral, 9 mm caudal and 3 mm ventral; somatosensory cortex, 2 mm lateral, 1.5 mm caudal and 2 mm ventral; auditory cortex: 6 mm lateral, 6 mm caudal and 5 mm ventral with a 20◦ medio-lateral angle. The enamel was removed from the bottom 0.5 mm of the intracranial recording electrode tip. The other tip of the electrode was connected to a micro-connector pin. One of the remaining pins was connected to a screw placed in the frontal bone and acted as the earth. Another pin was connected to a screw placed equidistant from the 3 electrodes and served as the voltage reference electrode. The electrodes, micro-connector and screws were sealed with dental cement.
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Fig. 1. Aspect of the lesions according to RMI. Upper pictures: MRI of a typical lesion. The arrows point to the lesioned part of the ventral hippocampus. Lower drawings: Minimum and maximum extent of the lesions considered for the purpose of the experiments. In the upper and lower drawings, coronal sections were adapted from those of Paxinos and Watson [74]. The distance from Bregma is indicated under each section. Abbreviations: fr: fasciculus retroflexus; ml: medial lemniscus; mp: mammillary peduncle; PAG: periaqueductal grey; SN: substantia nigra.
2.5.2. Evoked potential recording sessions A computer triggered light produced by a series of high-intensity white light emitting diodes (onset latencies in the s range), a white noise generator connected to a loudspeaker at the bottom of the test cage (onset latency in the ms range), or an electromagnet fixed vertically to a platform on which the rat was standing (onset latency in the ms range). Each of these stimulating devices was placed in a specific test cage. The three test cages were all the same size (vertical cylinder 40 cm high and 20 cm in diameter). The visual stimulation test cage was surrounded by a sheet of light-reflective aluminium paper. The bottom of the auditory stimulation test cage was a grid separating the rat from the membrane of the loudspeaker. The bottom of the tactile stimulation cage was made from a disc of Plexiglas held in place by 4 springs. The middle of it was connected to the core of the electromagnet. The stimulus-delivering interface was calibrated to deliver stimuli of 5 different strengths, as follows: light measured at the usual place of a rat’s eyes → 400, 150, 30, 10, 3 cd/m2 ; sound measured at the usual place of a rat’s ears → 105, 95, 85, 75, 65 dB(A); pressure of the moving platform → 3100, 1500, 600, 200, 100 N/m2 . The response of each brain site was assessed for the 5 stimulus strengths in random sequence. The brain electrodes were connected to an amplifier (PsyLab, Gain ×20 000, bandwidth: 0.1–40 Hz), the two channels of which were connected to the relevant electrode and to one of the other electrodes so that two evoked responses were recorded at once, the targeted response and another one as a control for the purpose of checking the topographical specificity of the evoked response. An evoked potential was obtained only with the relevant electrode except when the auditory cortex was considered and a tactile stimulus applied (NB, the movement of the device delivering the tactile stimulus was somewhat noisy). The amplifier outputs were connected to a 12-bit analogue–digital converter. A digital output channel of this interface was used to trigger visual, auditory or tactile stimuli depending on the electrode selected. This was controlled by a home-made LabView (National Instruments) program, which delivered 50 stimuli, each lasting 400 ms, with one every 3–5 s (randomized intervals), and recorded the subsequent evoked potential for a period of 125 ms (measurement frequency = 1000 Hz). The recordings were examined and added up, except in the case of saturation (less then 5% of cases). The resulting mean evoked potential was stored for further analyses. 2.5.3. Data analyses The latency (from the onset of the stimulus to the beginning of the evoked response (P1 wave) and amplitude (maximum evoked P1–N1 potential change) were measured for each electrode and each level of stimulus. The relationship
between the amplitude of the evoked potential response and strength of the stimulus was drawn on a graph. The stimulus threshold and slope of the transfer function, representing the sensitivity of the sensory system considered, were determined directly from the graph (in exactly the same way as in [38]). These parameters were subjected to t-tests (StatView software), with lesion status as the controlled variable (NVHL versus sham-lesioned). 2.5.4. Sensory gating experiment In a final experiment, two 80 dB(A), 1 ms pulses were interspaced by a 100 ms interval. The two subsequent evoked potentials were recorded and compared. Since the variances were correlated with the amplitudes, they were not directly suitable for an ANOVA. However, an ANOVA was performed on the logarithm of the amplitudes, with the two consecutive evoked potentials as within-group variable and lesion status as between-group controlled variable. We also submitted the means of individual differences to a t-test.
3. Results 3.1. Reaction to thermal and mechanical stimuli applied to the hind paws 3.1.1. Plantar test The lesion had a significant effect on withdrawal latency (F(2,24) = 36.54, p < 0.0001) with no difference between paws (F(1,24) = 0.97). The testing sequence yielded a significant effect (F(2,48) = 5.62, p < 0.01), but its interaction with the lesion was not significant (F(4,48) = 2.5). Mean latencies with the testing series also revealed a significant effect of lesion (F(2,24) = 36.53, p < 0.0001), due to a difference between NVHL and sham-lesioned rats (p < 0.0001) as well as between NVHL and non-operated controls (p < 0.0001), but not between sham-lesioned rats and nonoperated controls (p 0.99). As the bar graph to the left of Fig. 2 shows, withdrawal latency was shorter in NVHL rats, an indication of hyperreactivity to thermal stimulation.
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withdrawal response could be elicited in NVHL rats, an indication of hyposensitivity to mechanical pain. 3.2. Evoked potentials 3.2.1. Single auditory stimuli Fig. 3 illustrates the method used to analyze the evoked potentials on a representative result obtained with a sham-lesioned rat. The upper graph series are the mean evoked potentials as recorded in the auditory cortex (through the filter of the EEG recording system). The amplitudes appeared as a linear function of the stimulus strength (expressed in dB, the actual relationship being logarithmic). In this example of a typical “throughput” relationship the threshold was about 60 dB(A) (the mean threshold in sham-lesioned rats was 64 dB(A)). The thresholds for all rats that provided valid throughput functions (NVHL N = 8, Sham N = 8) differed between the NVHL and sham-lesioned rats (t = −2.32, p < 0.05), as illustrated at the bottom right of Fig. 3, the NVHL being 10 dB(A) less sensitive to the noises. Neither the slope of the throughput function (t = −0.86), nor latency (t = 1.9) differed. The mean latency was 8 ms. Fig. 2. Responses to painful stimuli. Bars in the left bar graph denote means (+SEM) of the latency to withdraw the hind paw in the plantar test (in seconds). Bars of the right bar graph denote means (+SEM) of the force that has to be applied to the plantar part of the hind paw with a von Frey hair to trigger its withdrawal. NVHL rats were compared to both sham lesioned rats and non-operated controls (***p < 0.001).
3.1.2. von Frey test The lesion had a significant effect on the strength of the stimulus that had to be applied before eliciting a withdrawal reaction (F(2,24) = 18.27, p < 0.0001). There was no difference between paws (F(1,24) = 3.52), and the test sequence was not significant (F(4,96) = 0.18). The lesion had a significant effect on mean strength (F(2,24) = 18.27, p < 0.0001), due to a difference between NVHL and sham-lesioned rats (p < 0.001) as well as between NVHL and nonoperated controls (p < 0.0001), but not between sham-lesioned rats and non-operated controls (p 0.46). As shown in the bar graph to the right of Fig. 2, a harder von Frey hair had to be used before a
3.2.2. Single visual stimuli In the cases that provided an acceptable throughput function when the response to light was tested (NVHL N = 6, Sham N = 7), there was no difference between the NVHL and sham-lesioned rats in terms of threshold (t = 0.56), sensitivity (t = 0.56), or latency (T = −0.07). The mean latency was 27 ms. 3.2.3. Single tactile stimuli In the cases that provided an acceptable throughput function when the response to a tactile stimulus was tested (NVHL N = 9, Sham N = 8), there was no difference between the NVHL and shamlesioned rats in terms of threshold (t = 0.70), sensitivity (t = 1.04), or latency (T = −1.10). The mean latency was 16 ms. 3.2.4. Sensory gating experiment As indicated in the previous section on auditory evoked potentials, 8 NVHL and 8 sham rats were used. There was a significant
Fig. 3. Auditory evoked potentials. The 5 upper graphs correspond to an example of evoked potentials in microvolt in a control rat, the y axis being the same for all graphs. The x axis is the time elapsed after application of the stimulus. Each evoked potential was triggered by a sound the loudness of which is indicated in dB(A) to the top right of each graph. The dotted line signals the beginning of the response. P1 and N1 were the waves considered in this study. The amplitude of the response corresponds to the P1–N1 difference as indicated by the vertical line with arrows. Amplitudes were plotted as a function of the loudness of the sound below to the left. The mean intercepts (+SEM) of this relationship with the x axis, i.e. the evoked potential threshold, for all rats considered are plotted on a bar graph to the bottom right.
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Fig. 4. Sensory gating. The mean evoked potentials (+ or − SEM) obtained after a first sound (1) and after a second sound occurring 100 ms later (2) are represented as the left hand bar graph for sham-lesioned and NVHL rats. The grey arrow shows the sensory gating effect of sham-lesioned rats. The right hand bar graph illustrates the means of the individual 1 → 2 differences for sham-lesioned and NVHL rats.
interaction between the lesion and two successive responses (F(1,16) = 5.19, p < 0.05). With respect to the individual ratios, i.e. where each subject was its own reference, and when these ratios were compared in a t-test for NVHL and sham-lesioned rats, the result was also a significant difference (t = 2.28, p < 0.05). The ANOVA showed no overall difference between either NVHL and sham-lesioned rats (F(1,16) = 0.33), or the responses to the first and second acoustic pulse (F(1,16) = 0.67), which is understandable given the data shown in Fig. 4. The bar graph on the left hand side shows the usual drop in the response between the first and second stimulus in sham-lesioned rats, a drop not seen in NVHL rats, whose response remained low in keeping with their lower reactivity to acoustic stimuli The ratios represented on the right hand side depict the mean individual differences and show that, contrary to the standard reduction in control rats from one stimulus to the next, in NVHL rats the response even tended to increase. 3.3. RMI and histological observations The lesions were the same size as those considered in our previous studies and correspond to the description given in Al Amin et al.’s [36] report. 4. Discussion 4.1. Reaction to painful stimuli in lower animal models of schizophrenia Modified responsiveness to painful stimuli in lower animal models of schizophrenia has been regularly reported, but the modification has varied according to (i) the model, (ii) type of pain considered, and (iii) evaluation method used. Thermal hyperalgesia has already been reported in NVHL rats, in a study that used the same lesion sizes and evaluation methods as the present study [36], but their reactivity to painful mechanical stimuli remained unaltered. The rats, it is worth noting, were handheld, paw pinches were used rather than calibrated stimuli, and the focus was on withdrawal latency rather than pain threshold, but the fact remains that both studies point to a differential reactivity to thermal versus mechanical pain. Such differential responsiveness to distinct types of pain has seldom been reported. Nevertheless, recent observations pointed to dissociations, such as hyporeactivity to cold painful stimuli (tested by topical application of menthol) but no change in reactivity to mechanical painful stimuli [39], and the abolition of thermal pain and reduced reactivity to noxious
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mechanical stimuli without any change in the reactivity to hot or cold pain [40], this change ensuing from genetic modification of pain detecting neurons. Such examples indicate that the three pain types may work independently of each other in natural living conditions. But an alternative explanation for the dissociation we observed must be considered. A withdrawal reaction to heat is no more than a reflex organized at the level of the spinal chord, whereas the complex behavioural expression of unpleasantness triggered by painful mechanical stimuli requires a higher level of organization. Many other lower animal modelling strategies have been used in studies on schizophrenia, involving submitting animals to social deprivation, modifying their genome, or administering psychoactive drugs (review in: [41]). Social deprivation in the peripubertal period produced hyperalgesia [42,43], as did deleting the “schizophrenia-associated gene”, COMT, or the STOP cytoskeleton gene [44]. Deleting other “schizophrenia-associated genes”, such as NRG1 and DISC1, resulted on the contrary in hypoalgesia [45]. Psychoactive drugs, for instance indirect dopamine agonists or NMDA receptor antagonists, elicited hypoalgesia [46–49]. Insofar as NMDA antagonists are anaesthetics, this was hardly surprising. What common neurobiological substrate would be compatible with the diversity of this modified reactivity to pain? Experiments focusing on the role of the dopaminergic mesocorticolimbic system in the reaction to pain have provided interesting data in this respect. Amphetamine-induced hypoalgesia in rats turned into hyperalgesia after 6-hydroxydopamine lesions were performed in the ventral tegmental area [46], an indication that the functional status of the mesocorticolimbic dopaminergic system, which is dysfunctional in patients, could tip the scale of nociception. 4.2. Pain perception in patients with schizophrenia There are three lines of argument that support the occurrence of hypoalgesia in schizophrenia: (i) clinical case reports, according to which some patients feel little or no pain [50–52], (ii) population-based studies indicating a low prevalence of schizophrenia diagnosis in pain patients [51,53,54], and (iii) experimental studies showing increased pain thresholds in patients [13,14]. Moreover, according to a recent meta-analysis hypoalgesia is one of several manifestations of blunted responses to primary bodily sensations in these patients [13]. Recent studies, including functional imaging methods, have shown that pain tolerance to heat was slightly higher in patients (1.3 ◦ C), with no difference between them and controls as regards either their perception of pain intensity or unpleasantness [14]. In summary, only moderate changes in perception thresholds were observed in patients, in contrast to the occasionally dramatic insensitivity to pain reported in published “case reports” [51,54]. How can a minor sensory deficit become a total sensory neglect? If we assume that the reduced sensitivity to pain reflected enhanced basal hyperactivity of the internal antinociceptive system, it is easy to accept that any situation which triggers an internal antinociceptive response, such as stress, would also enhance that response far more in patients than in healthy persons. It would be interesting to test this hypothesis and understand how such peaks of activity are triggered. The mesolimbic dopaminergic system might be involved, as indicated in the previous chapter of this discussion. An experimental approach using lower animal models could be helpful to that end. 4.3. Extension of the observations to other sensory systems It was not only patients’ pain threshold that was higher but also their basic thermal sensation [55,56]. Furthermore, evoked potential studies also produced evidence of hearing and sight
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deficits [12,38,57–62]. Characterizing NVHL rats’ responsiveness to auditory, visual and tactile stimuli was therefore justified. We found a higher threshold only for auditory evoked response. Evoked potential responses to light and tactile stimuli in NVHL rats were unchanged, but these negative results should be seen with caution, because it is possible the evoked potential method is not sensitive enough to cope with these sensory modalities in albino rats. The reduced sensitivity to sounds found in this study would contradict our previously reported facilitation of reactivity to sounds in NVHL rats [20]. However, the behavioural response considered in these previous studies, consisting of compulsive running triggered by very loud noises, was considered to result from attenuated thalamo-collicular top-down control, a thesis which ties in with modified thalamo-cortical systems observed in patients combined with bottom-up information flow attenuation [63,64]. Our findings suggest it would be helpful to test features common to different sensory modalities in patients, for example the threshold when acoustic or visual stimuli become uncomfortable or painful, including in the test conditions where such transitions would be modified, for instance by manipulating their emotional status. We found no change in visual or tactile evoked potentials in NVHL rats. As far as we are aware from the literature, no such research has ever been conducted on lower animal models of schizophrenia. With respect to the tactile modality, modified spatial distribution of evoked potentials has been reported in patients [65,66]. The “cross-talk” we observed between acoustic and tactile evoked potentials, attributed in Section 3 to the noise produced by the tactile stimulation device, could alternatively result from such modified spatial distribution of the evoked potentials. This would warrant better assessment with the help of specific research involving simultaneous recording in numerous brain sites and spatial reconstructions in NVHL rats. 4.4. Sensory gating in models of schizophrenia and in patients Sensory gating attenuation in NVHL rats had already been clearly demonstrated, but relied on a behavioural criterion, the startle reflex (review in: [15,16]). It was also tested more recently using evoked potential by Vohs et al. [32]. Their raw data in table 1 of their publication look like our own, namely the response to the first stimulus was reduced in NVHL rats and, subsequently, the ratio between the response to the first and second stimuli was lower. However, the results obtained by Vohs et al. did not attain statistical significance except when more refined analyses were conducted. Another neuro-developmental model showed exactly the same sensorygating deficit, including the weaker evoked potential observed after the first of the two acoustic pulses [30]. Pharmacological models provide the same picture [30,67,68]. Meta-analyses show that the amplitude of evoked auditory waves was reduced in patients and coupled with impaired sensory-gating, even though not observed in every study [58,69,70]. In addition, Vohs et al. also found an inconstant response latency in NVHL rats (reported as “a lower phase reproducibility”). This means that the individual evoked responses would be more scattered, and, consequently, the summation process used to evaluate the mean amplitudes would inevitably produce a lower amplitude. Vohs et al. suggest this reflects an inability on the part of NVHL rats and patients to desynchronize quickly from external sensory stimulation as a result of minor disturbances in their cortex neuronal networks [32]. 4.5. Are these observation relevant only for schizophrenia? Modified pain sensitivity is one of the manifestations of Rett syndrome, a severe neuro-developmental disorder [71]. Heightened pain stimuli tolerance was also found in almost 90% cases of children with Phelan-McDermid syndrome, with enhanced
responsiveness to tactile and acoustic stimuli and preserved visual capacities [71]. Insensitivity to pain was found in other disorders, such as a familial dysautonomia, Prader-Willi syndrome and Williams syndrome, together with acoustic hyperreactivity [71]. About 40–70% of children with autism display some abnormality as regards their sensory sensitivity. For them, sudden and unexpected noises can be unbearable. They also often show no reaction to pain and high/low temperatures [72]. This brief review indicates that the same set of sensory modifications was found in several different neuro-developmental diseases, suggesting that our observations with the NVHL model should not be confined to speculations about schizophrenia but could be extended to include other neuro-developmental diseases [73]. 5. Conclusion Animals used as models and patients with schizophrenia, display minor sensory deficits. Convergences between NVHL rats and schizophrenia consisted of attenuated acoustic perception, suppression of sensory-motor gating, and lower reactivity to painful mechanical stimuli. Divergence was confined to enhanced reactivity to heat pain. In general, it reflects a minor but general functional sensory system perturbation. This point of view applies also to the reduced cortical sensory gating phenomenon. Similar perturbations are also found in other developmental diseases. Conflict of interest The authors hereby declare that, other than income received from their main employer, they have received no financial support or compensation from any individual or corporate entity over the past 3 years for research or professional services, and that there are no personal financial holdings that could be perceived as constituting a potential conflict of interest. Financial disclosure This work was funded by INSERM and the University of Strasbourg, France. These institutional funding bodies played no further role in the study design, data collection, analysis, or interpretation, report writing, or decision to submit the paper for publication. Acknowledgements We would like to thank Julien Gobaille and Jacques Knobloch for having looked after the dams and pups so well until they reached adulthood. The RMI images were obtained by courtesy of the Strasbourg Plateforme d’Imagerie in Vivo, LINC, campus médecine, IFR 37 de Neurosciences de Strasbourg. Help with the English language was provided by Mrs Gillian Wakenhut. References [1] Harrison PJ. Schizophrenia: a disorder of neurodevelopment. Current Opinion in Neurobiology 1997;7:285–9. [2] Schultz SK, Andreasen NC. Schizophrenia. Lancet 1999;353:1425–30. [3] Lewis DA, Lieberman JA. Catching up on schizophrenia: natural history and neurobiology. Neuron 2000;28:325–34. [4] Ashe PC, Berry MD, Boulton AA. Schizophrenia, a neurodegenerative disorder with neurodevelopmental antecedents. Progress in NeuroPsychopharmacology and Biological Psychiatry 2001;25:691–707. [5] Mechri A, Bourdel MC, Slama H, Gourion D, Gaha L, Krebs MO. Neurological soft signs in patients with schizophrenia and their unaffected siblings: frequency and correlates in two ethnic and socioeconomic distinct populations. European Archives of Psychiatry and Clinical Neuroscience 2009;259:218–26. [6] Van Os J. Are psychiatric diagnoses of psychosis scientific and useful? The case of schizophrenia. Journal of Mental Health 2010;19:305–17.
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