Sex-specific alterations in behavioral and cognitive functions in a "three hit" animal model of schizophrenia.

Whereas schizophrenia affects both human sexes, there are known sex-dependent disparities. We developed a chronic animal model that shows some schizophrenia-related deficits in rats by applying selective breeding after subchronic ketamine administration connected with postweaning social isolation (complex treatment). Our aim was to determine the sex-specific effects of these interventions on several processes. Sensory gating to acoustic stimulation, pain sensitivity, motor behavior, spatial learning and memory deficits on the hole-board test were assessed in the 17th generation of selectively bred Wistar rats compared to their naive counterparts with or without complex treatment. We found differences between the sexes: selectively bred males with complex treatment showed the lowest pain sensitivity; however, the results of the prepulse inhibition test indicated that female rats showed enhanced impairment of sensory gating and increased acoustic startle reaction. The cognitive performance, working and reference memory ratios were significantly decreased by selective breeding and showed sex-specific alterations, with the smallest value in male rats of the new substrain. Based on these results, the animals of the new substrain could be classified into the high-risk for schizophreniform phenotype with the highest sensitivity of males with complex treatment. Decreased cognitive performance highlighted spatial learning deficits in the selectively bred and treated rats that escalate the validity of our new and complex rat model of schizophrenia. The results indicate the same sex selectivity as observed in humans, with increased incidence of risk ratios for men to develop schizophrenia relative to women.

Co-oscillation and synchronization between the posterior thalamus and the caudate nucleus during visual stimulation.

Recent results suggest significant cross-correlation between the spike trains of the suprageniculate nucleus (SG) of the posterior thalamus and the caudate nucleus (CN) during visual stimulation. In the present study visually evoked local field potentials (LFPs) were recorded simultaneously in the CN and the SG in order to investigate the coupling between these structures at a population level. The effect of static and dynamic visual stimulation was analyzed in 55 SG-CN LFP pairs in the frequency range 5-57Hz. Statistical analysis revealed significant correlation of the relative powers of each investigated frequency band (5-8Hz, 8-12Hz, 12-35Hz and 35-57Hz) during both static and dynamic visual stimulation. The temporal evolution of cross-correlation showed that in the majority of the cases the SG was activated first, and in approximately one third of the cases, the CN was activated earlier. These observations suggest a bidirectional information flow. The most interesting finding of this study is that different frequency bands exhibited significant cross-correlation in a stimulation paradigm-dependent manner. That is, static stimulation usually increased the cross-correlation of the higher frequency components (12-57Hz) of the LFP, while dynamic stimulation induced changes in the lowest frequency band (5-8Hz). This suggests a parallel processing of dynamic and static visual information in the SG and the CN. To our knowledge we are the first to provide evidence on the co-oscillation and synchronization of the CN and the SG at a population level upon visual stimulation, which suggests a significant cooperation between these structures in visual information processing.

Overlap of nigrothalamic terminals and thalamostriatal neurons in the feline lateralis medialis-suprageniculate nucleus.

The lateralis medialis-suprageniculate nucleus (LM-Sg) of the feline posterior thalamus is a relay nucleus with a clear visuomotor function. In this study, we examined the distribution of axon terminals of the nigral afferent to the LM-Sg following injection of an anterograde tracer, biocytin, into the substantia nigra pars reticulata, and the distribution of the thalamostriatal projection neurons in the LM-Sg following the injection of wheat germ agglutinin conjugated with horseradish peroxidase (WGA-HRP) as a retrograde tracer into the caudate nucleus. The biocytin-labeled terminal-like puncta were located in the ventromedial portion of this nucleus in such a way that most of the labeled elements took the form of swellings having boutons in places, while a minority appeared in clusters of 3-5 large terminal-like puncta. The retrograde WGA-HRP-labeled neurons were also found in the ventromedial part of the LM-Sg, and the distributions of labeled nigrothalamic axon terminals and labeled thalamostriatal projection neurons therefore overlapped in this region. The present results indicate that the nigral afferent may make synaptic contacts directly with the thalamostriatal projection neurons within the LM-Sg.

Spatial and temporal visual properties of single neurons in the suprageniculate nucleus of the thalamus.

The spatial and temporal visual sensitivity to drifting sinusoidal gratings was studied in 105 neurons of the suprageniculate nucleus of the feline thalamus. Extracellular single-unit recordings were performed in halothane-anesthetized, immobilized, artificially ventilated cats. Most suprageniculate nucleus cells were strongly sensitive to the direction of drifting gratings. The suprageniculate nucleus units had a clear preference for very low spatial frequencies with a mean of 0.05 cycle/deg. The spatial resolution was also very low with a mean of 0.16 cycle/deg. Most of the cells displayed low-pass spatial tuning characteristics, while the remainder of the units were band-pass tuned. The suprageniculate nucleus units were extremely narrowly tuned, to spatial frequencies with a mean spatial bandwidth of 1.07 octaves. A majority of the units responded optimally to high temporal frequencies, with a mean of 8.53 Hz. The temporal frequency tuning functions predominantly revealed a band-pass character, with a mean temporal bandwidth of 1.66 octaves. These results demonstrate that the neurons in the suprageniculate nucleus display particular spatial and temporal characteristics. The spatial and temporal tuning properties of the suprageniculate nucleus neurons are very similar to those of the superior colliculus and the anterior ectosylvian cortex, structures that provide the main visual afferentation toward the suprageniculate nucleus. This suggests their common function in motion perception, and especially in the recording of movements of the visual environment relative to the body, and the related behavioral action.

Mechanisms of within- and cross-modality suppression in the superior colliculus.

The present studies were initiated to explore the basis for the response suppression that occurs in cat superior colliculus (SC) neurons when two spatially disparate stimuli are presented simultaneously or in close temporal proximity to one another. Of specific interest was examining the possibility that suppressive regions border the receptive fields (RFs) of unimodal and multisensory SC neurons and, when activated, degrade the neuron's responses to excitatory stimuli. Both within- and cross-modality effects were examined. An example of the former is when a response to a visual stimulus within its RF is suppressed by a second visual stimulus outside the RF. An example of the latter is when the response to a visual stimulus within the visual RF is suppressed when a stimulus from a different modality (e. g., auditory) is presented outside its (i.e., auditory) RF. Suppressive regions were found bordering visual, auditory, and somatosensory RFs. Despite significant modality-specific differences in the incidence and effectiveness of these regions, they were generally quite potent regardless of the modality. In the vast majority (85%) of cases, responses to the excitatory stimulus were degraded by >/=50% by simultaneously stimulating the suppressive region. Contrary to expectations and previous speculations, the effects of activating these suppressive regions often were quite specific. Thus powerful within-modality suppression could be demonstrated in many multisensory neurons in which cross-modality suppression could not be generated. However, the converse was not true. If an extra-RF stimulus inhibited center responses to stimuli of a different modality, it also would suppress center responses to stimuli of its own modality. Thus when cross-modality suppression was demonstrated, it was always accompanied by within-modality suppression. These observations suggest that separate mechanisms underlie within- and cross-modality suppression in the SC. Because some modality-specific tectopetal structures contain neurons with suppressive regions bordering their RFs, the within-modality suppression observed in the SC simply may reflect interactions taking place at the level of one input channel. However, the presence of modality-specific suppression at the level of one input channel would have no effect on the excitation initiated via another input channel. Given the modality-specificity of tectopetal inputs, it appears that cross-modality interactions require the convergence of two or more modality-specific inputs onto the same SC neuron and that the expression of these interactions depends on the internal circuitry of the SC. This allows a cross-modality suppressive signal to be nonspecific and to degrade any and all of the neuron's excitatory inputs.

Bilateral projections from the superior colliculus to the suprageniculate nucleus in the cat: a WGA-HRP/double fluorescent tracing study.

Following WGA-HRP injection into the right suprageniculate nucleus of the cat brain, retrogradely-labeled neurons were found not only in the ipsilateral, but also in the contralateral superior colliculi. After WGA-HRP injection into the unilateral superior colliculus, anterogradely-labeled axon terminals were observed in the bilateral suprageniculate nuclei, and electron microscopic examination revealed that these were large terminals which made asymmetric synaptic contacts with dendrites. When a different kind of fluorescent tracer was injected into each suprageniculate nucleus (Fast blue and Nuclear yellow), double-labeled neurons were observed in the rostral and middle portions of both superior colliculi. These results suggest that there are direct bilateral projections from the superior colliculus to the suprageniculate nuclei, and that some of these projections originate from branching colliculo-suprageniculate axons.

Organization of cortical and subcortical projections to the feline insular visual area, IVA.

Extracellular recordings with carbon fiber-filled microelectrodes were used to identify the visually responsive area within the insular cortex (referred to hereafter as the insular visual area, IVA) of anaesthetized cats. Broadly speaking, IVA comprises the cortex surrounding the anterior ectosylvian sulcus (AEs) along its ventral bank and the major portion of the anterior sylvian gyrus. Visually sensitive cells were recorded along the whole length of the AEs. In the same animals, the afferent connections of IVA were studied through the use of the retrograde tracers wheat germ agglutinin-conjugated horseradish peroxidase (WGA-HRP) and fluorescent Diamidino yellow (DY), in combination with standard electrophysiological stimulation and recording techniques. The results indicate that: (1) the IVA receives a wide variety of telencephalic inputs, not only from visual, sensorimotor, auditory, limbic and association cortical areas, and from the claustrum, amygdala and basal nucleus of Meynert, as well, but also from the diencephalic projections arising mainly from the lateralis medialis-suprage niculate nuclear complex (LM-Sg) and the ventral medial nucleus (VM). (2) The gyral part of IVA (gIVA) receives afferents mainly from the lateral part of the lateral suprasylvian visual area (LS) throughout almost its entire length, as well as from area 20, the posterior suprasylvian sulcal area (PS), the frontal eye fields, areas 6 and 36, and almost the whole length of the cortical area lying along the anterior ectosylvian sulcus (AEs). (3) By contrast with (2), the sulcal part of IVA (sIVA) which corresponds to the anterior part of the anterior ectosylvian visual area (AEV) of Norita et al. ('86), receives cortical projections mainly from the lateral and medial parts of the anterior half of LS, area 20, PS, the frontal eye fields, area 36, and most parts of the cortical area extending along the AEs. (4) Subcortically, IVA receives thalamic afferents mainly from VM and LM-Sg. The connections between IVA and LM-Sg are organized topographically, with the more anterior part of IVA being related to the more ventral portion of LM-Sg, and with sIVA being related chiefly to the mid-portions of LM-Sg. These results thus suggest that IVA may function as an integrative centre among structures belonging to the extrageniculostriate system, the sensorimotor system, as well as to the limbic system. Furthermore, our electrophysiological and anatomical findings, together with previous reports concerning AEV, suggest that the posterior part of AEV (AEV proper) is distinctive from gIVA, and that the sIVA apparently serves as a transitional region between AEV and gIVA.

Cholecystokinin interferes with the thermoregulatory effect of exogenous and endogenous opioids.

Intraperitoneal (ip) injection of cholecystokinin octapeptide sulfate ester (CCK; 5, 10 and 50 micrograms/kg) reduced the hypothermic response to 8 mg/kg and 32 mg/kg systemic morphine in restrained and freely moving rats, respectively. The hyperthermia elicited by a subcutaneous (sc) injection of 8 mg/kg morphine to freely moving rats was not diminished by CCK pretreatment. CCK (5 micrograms/kp ip) completely prevented the restraint stress-induced hyperthermia. Naloxone (1 mg/gk sc) was effective in antagonizing both the hyperthermic and the hypothermic effects of morphine and the stress-induced emotional hyperthermia. These results support the hypothesis that CCK may contribute to regulation of the endogenous opioid system.

Connections of the anterior ectosylvian visual area (AEV).

We have previously described a visual area situated in the cortex surrounding the deep infolding of the anterior ectosylvian sulcus of the cat (Mucke et al. 1982). Using orthograde and retrograde transport methods we now report anatomical evidence that this anterior ectosylvian visual area (AEV) is connected with a substantial number of both cortical and subcortical regions. The connections between AEV and other cortical areas are reciprocal and, at least in part, topographically organized: the rostral AEV is connected with the bottom region of the presylvian sulcus, the lower bank of the cruciate sulcus, the rostral part of the ventral bank of the splenial sulcus, the rostral portion of the lateral suprasylvian visual area (LS) and the lateral bank of the posterior rhinal sulcus; the caudal AEV is connected with the bottom region of the presylvian sulcus, the caudal part of LS, the ventral part of area 20 and the lateral bank of the posterior rhinal sulcus. Subcortically, AEV has reciprocal connections with the ventral medial thalamic nucleus (VM), with the medial part of the lateralis posterior nucleus (LPm), as well as with the lateralis medialis-suprageniculate nuclear (LM-Sg) complex. These connections are also topographically organized with more rostral parts of AEV being related to more ventral portions of the LPm and LM-Sg complex. AEV also projects to the caudate nucleus, the putamen, the lateral amygdaloid nucleus, the superior colliculus, and the pontine nuclei. It is concluded that AEV is a visual association area which functionally relates the visual with both the motor and the limbic system and that it might play a role in the animal's orienting and alerting behavior.

Sensitization or tolerance to morphine effects after repeated stresses.

Rats were subjected to prolonged footshock, intensive acoustic stress, cold water swim and restraint over a period of 10 days. The analgesic and thermoregulatory properties of morphine (2, 4 and 8 mg/kg, sc.) were tested on the 11th day. Analgesia assessment was performed by means of hot-plate (HP) and tail-flick (TF) tests, and body temperature (Tb) changes was measured. Prolonged footshock and acoustic stress increased the sensitivity to morphine, while repeated restraint lessened morphine's effect. Cold water swim caused ambiguous consequences, facilitated the effect of a small dose of morphine, but reduced that of a large dose. It was concluded that the sensory components of the stressful exposure determine the effects of repeated stress on morphine sensitivity. Whereas painful interventions led to sensitization, and non-painful procedures result in tolerance to morphine's effects. The finding that analgesic and thermoregulatory effects of morphine were simultaneously enhanced supports the contention that the mechanism of sensitization to opiates involves a site where pathways mediating opiate analgesia and thermoregulatory effects converge.

Thermal and chemical stimulations of the hypothalamic heat detectors: the effects of the EEG.

In acute immobilized rats, the effect on the EEG of thermal and chemical (capsaicin microinjection) stimulation of the warm sensors in the preoptic region, mid-hypothalamic area and posterior hypothalamus were studied. Both localized heating and capsaicin resulted in a sleep-like EEG with spindles and slow waves. Stimulation of the posterior hypothalamus was the most effective and stimulation in the mid-hypothalamus was the least effective in inducing spindle activity. Since capsaicin is regarded as a specific stimulant for the hypothalamic warm sensors, the results suggest that the EEG effect, and probably the sleep-inducing effect, of heat are mediated via the central thermoreceptors, and cannot be due to a non-specific activation of the basal forebrain hypnogenic mechanisms.

Elevation of thermoregulatory vasodilatation threshold in the rat after capsaicin treatment.

In control and capsaicin-treated (300 mg/kg) rats tail skin vasodilatation was studied while the body temperature was raised to 38 degrees C, 39 degrees C or 40 degrees C and held at these levels. In the capsaicin-treated rats, at 38 degrees C vasodilatation was weaker than in the controls but at temperatures of 39 degrees C and 40 degrees C a delayed increase in tail vasodilatation occurred to the level observed in the controls. It is concluded that the threshold of vasodilatation response to heat is elevated after capsaicin treatment.

Evoked potential study of the synchronizing and hypnogenic areas in the basal forebrain.

On stimulating various basal forebrain structures, characteristic cortical evoked potentials, basic elements of the synchronization elicited, were studied in acute immobilized cats. Stimulation of the LH/10 cps/ resulted in short latency positive-negative evoked potentials, similar responses of increased latency were elicited from the RPO and TbOf. The laterobasal RPO and TbOf, the only areas able to induce cortical synchronization upon high frequency stimulation, could be clearly distinguished on the basis of evoked potentials. The laterobasal RPO was characterized by short latency, long-lasting positive potentials, while stimulation of TbOf elicited negative-positive responses. The relationship between the evoked potentials and the synchronizing mechanism of the basal forebrain is discussed.

The effect of high mesencephalic transection (cerveau isolé) and pentobarbital on basal forebrain mechanisms of EEG synchronization.

A study was made of the effects of high mesencephalic transection (cerveau isolé) and low doses of pentobarbital on the cortical synchronizations elicited in acute immobilized cats by (a) low frequency stimulation of the lateral hypothalamus (HL) and nucleus ventralis anterior thalami (VA) and (b) by low and high frequency stimulation of the laterobasal preoptic region (RPO) and olfactory tubercle (TbOf). The results obtained were as follows: (1) The synchronizations induced by basal forebrain stimulations were found to survive in acute cerveau isolé cats, moreover, even a facilitation of the synchronizing effect were observed. (2) A gradual facilitation was observed upon TbOf and RPO stimulation, while in the case of VA and HL stimulations, the facilitation appeared immediately after the transection. (3) Low doses of pentobarbital depressed the cortical effects of TbOf stimulation, while an increase of the synchronizing effect of low frequency VA and HL stimulation was found. The observations suggested that (i) the synchronizing mechanism in the ventral part of the basal forebrain (RPO and TbOf) differs from that of the thalamus and HL; (ii) the basal forebrain synchronizing mechanism is effective without the contribution of the brain stem; (iii) the mechanism responsible for the synchronizing effect of low frequency HL stimulation is similar as that described for the thalamus.

Cortical synchronization induced by thermal stimulation of the preoptic area in immobilized rats.

Cortical synchronization characterized by frontal spindles and occipital slow wave activity was induced by bilateral thermal stimulation of 2--4 degrees C of the preoptic area in unanaesthetized immobilized rats. The synchronization was demonstrated by ECoG and its power density spectra. The ECoG of the synchronization was similar to that of slow wave sleep. Switching off the thermal stimulation the original activity was recovered in most of the cases. Frontal spindle activity and slow wave activity recorded over the posterior cortex seemed to be dissociated to some degree. Low frequency stimulation at the points of thermal stimulation resulted in frequency following synchronization. In some cases electrical and thermal stimulation induced gradually developing seizure activity.