Sound frequency dependence of duration mismatch negativity recorded from awake rats.

AIMS: The brain function that detects deviations in the acoustic environment can be evaluated with mismatch negativity (MMN). MMN to sound duration deviance has recently drawn attention as a biomarker for schizophrenia. Nonhuman animals, including rats, also exhibit MMN-like potentials. Therefore, MMN research in nonhuman animals can help to clarify the neural mechanisms underlying MMN production. However, results from preclinical MMN studies on duration deviance have been conflicting. We investigated the effect of sound frequency on MMN-like potentials to duration deviance in rats. METHODS: Event-related potentials were recorded from an electrode placed on the primary auditory cortex of free-moving rats using an oddball paradigm consisting of 50-ms duration tones (standards) and 150-ms duration tones (deviants) at a 500-ms stimulus onset asynchrony. The sound frequency was set to three conditions: 3, 12, and 50 kHz. RESULTS: MMN-like potentials that depended on the short-term stimulus history of background regularity were only observed in the 12-kHz tone frequency condition. CONCLUSIONS: MMN-like potentials to duration deviance are subject to tone frequency of the oddball paradigm in rats, suggesting that rats have distinct sound duration recognition ability.

Neonatal exposure to an inflammatory cytokine, epidermal growth factor, results in the deficits of mismatch negativity in rats.

Perinatal exposure to epidermal growth factor (EGF) induces various cognitive and behavioral abnormalities after maturation in non-human animals, and is used for animal models of schizophrenia. Patients with schizophrenia often display a reduction of mismatch negativity (MMN), which is a stimulus-change specific event-related brain potential. Do the EGF model animals also exhibit the MMN reduction as schizophrenic patients do? This study addressed this question to verify the pathophysiological validity of this model. Neonatal rats received repeated administration of EGF or saline and were grown until adulthood. Employing the odd-ball paradigm of distinct tone pitches, tone-evoked electroencephalogram (EEG) components were recorded from electrodes on the auditory and frontal cortices of awake rats, referencing an electrode on the frontal sinus. The amplitude of the MMN-like potential was significantly reduced in EGF-treated rats compared with saline-injected control rats. The wavelet analysis of the EEG during a near period of tone stimulation revealed that synchronization of EEG activity, especially with beta and gamma bands, was reduced in EGF-treated rats. Results suggest that animals exposed to EGF during a perinatal period serve as a promising neurodevelopmental model of schizophrenia.

Epidermal growth factor signals attenuate phenotypic and functional development of neocortical GABA neurons.

Phenotypic development of neocortical GABA neurons is highly plastic and promoted by various neurotrophic factors such as neuregulin-1. A subpopulation of GABA neurons expresses not only neuregulin receptor (ErbB4) but also epidermal growth factor (EGF) receptor (ErbB1) during development, but the neurobiological action of EGF on this cell population is less understood than that of neuregulin-1. Here, we examined the effects of exogenous EGF on immature GABA neurons both in culture and in vivo and also explored physiological consequences in adults. We prepared low density cultures from the neocortex of rat embryos and treated neocortical neurons with EGF. EGF decreased protein levels of glutamic acid decarboxylases (GAD65 and GAD67), and EGF influences on neuronal survival and glial proliferation were negligible or limited. The EGF treatment also diminished the frequency of miniature inhibitory postsynaptic currents (mIPSCs). In vivo administration of EGF to mouse pups reproduced the above GABAergic phenomena in neocortical culture. In EGF-injected postnatal mice, GAD- and parvalbumin-immunoreactivities were reduced in the frontal cortex. In addition, postnatal EGF treatment decreased mIPSC frequency in, and the density of, GABAergic terminals on pyramidal cells. Although these phenotypic influences on GABA neurons became less marked during development, it later resulted in the reduced ß- and γ-powers of sound-evoked electroencephalogram in adults, which is regulated by parvalbumin-positive GABA neurons and implicated in the schizophrenia pathophysiology. These findings suggest that, in contrast to the ErbB4 ligand of neuregulin-1, the ErbB1 ligand of EGF exerts unique maturation-attenuating influences on developing cortical GABAergic neurons.

Chronic phencyclidine treatment induces long-lasting glutamatergic activation of VTA dopamine neurons.

Use of phencyclidine (PCP) can mimic some aspects of schizophrenia. However, the underlying mechanism is unclear. Administration of PCP is known to activate mesolimbic dopamine pathway. In this study, we focused on ventral tegmental area (VTA) of mesolimbic dopamine pathway as target of PCP for inducing schizophrenia-like symptoms. Single VTA neuron was isolated and its neural activity was monitored by measuring cytosolic Ca(2+) concentration ([Ca(2+)]i) followed by immunocytochemical identification of dopamine neurons. Administration of glutamate increased [Ca(2+)]i in dopamine neurons from control rats, and the [Ca(2+)]i increase was inhibited in the presence of PCP. In contrast, in VTA dopamine neurons from rats chronically treated with PCP for 7 days, administration of glutamate was able to induce [Ca(2+)]i increase in the presence of PCP. Furthermore, this glutamate-induced [Ca(2+)]i increase in the presence of PCP continued even after washout of glutamate and this effect lasted as long as PCP was present. This long-lasting glutamate-induced [Ca(2+)]i increase in the presence of PCP was not observed or significantly attenuated under Ca(2+) free condition and by N-type Ca(2+) channel blocker ω-conotoxin. The results indicate that chronic treatment with PCP reverses the acute PCP effect on VTA dopamine neurons from inhibitory to stimulatory tone, and consequently induces long-lasting activation of dopamine neurons by glutamate.

The role of the hippocampo-prefrontal cortex system in phencyclidine-induced psychosis: a model for schizophrenia.

Phencyclidine (PCP) is a psychotomimetic drug that induces schizophrenia-like symptoms in healthy individuals and exacerbates pre-existing symptoms in patients with schizophrenia. PCP also induces behavioral and cognitive abnormalities in non-human animals, and PCP-treated animals are considered a reliable pharmacological model of schizophrenia. However, the exact neural mechanisms by which PCP modulates behavior are not known. During the last decade several studies have indicated that disturbed activity of the prefrontal cortex (PFC) may be closely related to PCP-induced psychosis. Systemic administration of PCP produces long-lasting activation of medial PFC (mPFC) neurons in rats, almost in parallel with augmentation of locomotor activity and behavioral stereotypies. Later studies have showed that such PCP-induced behavioral abnormalities are ameliorated by prior administration of drugs that normalize or inhibit excess excitability of PFC neurons. Similar activation of mPFC neurons is not induced by systemic injection of a typical psychostimulant such as methamphetamine, even though behavioral hyperactivity is induced to almost the same level. This suggests that the neural circuits mediating PCP-induced psychosis are different to those mediating methamphetamine-induced psychosis. Locally applied PCP does not induce excitation of mPFC neurons, indicating that PCP-induced tonic excitation of mPFC neurons is mediated by inputs from regions outside the mPFC. This hypothesis is strongly supported by experimental results showing that local perfusion of PCP in the ventral hippocampus, which has dense fiber projections to the mPFC, induces tonic activation of mPFC neurons with accompanying augmentation of behavioral abnormalities. In this review we summarize current knowledge on the neural mechanisms underlying PCP-induced psychosis and highlight a possible involvement of the PFC and the hippocampus in PCP-induced psychosis.

Role of the lateral preoptic area and the bed nucleus of stria terminalis in the regulation of penile erection.

To elucidate the role of the preoptic area (POA) in the regulation of penile erection, we examined the effects of electrical stimulation in and around the POA on penile erection in rats, which was assessed by changes in pressure in the corpus spongiosum of the penis (CSP) and electromyography (EMG) of the bulbospongiosus (BS) muscle. In unanesthetized and anesthetized rats, four types of responses were induced by stimulation in and around the POA; (1) normal type responses, which were similar to spontaneously occurring erections, characterized by slow increase in CSP pressure and sharp peaks concurrent with BS muscle bursting; (2) muscular type responses, which included sharp CSP pressure peaks (muscular component) with almost no vascular component; (3) mixed type responses, which included a sequence of high-frequency CSP peaks followed by low-frequency CSP peaks; and (4) micturition type responses, which had higher-frequency and lower-amplitude CSP peaks than other responses which were identical to those of normal micturition. In unanesthetized condition, erections were evoked by stimulation of the lateral preoptic area (LPOA), medial preoptic area (MPOA), bed nucleus of the stria terminalis (BST), paraventricular nucleus (PVN), reuniens thalamic nucleus (Re) and lateral septum (LS). Lower-intensity stimulation evoked erections from the LPOA, BST, PVN and RE, but not the MPOA. In anesthetized condition, stronger stimuli were required and effective sites were restricted to the LPOA, MPOA and BST. These findings suggest that the lateral and medial subdivisions of the preoptic area play different roles in mediating penile erection.

Penile erection and micturition events triggered by electrical stimulation of the mesopontine tegmental area.

The cholinergic neurons in the laterodorsal tegmental nucleus (LDT) play a crucial role in the regulation of rapid eye movement (REM) sleep. Because penile erection occurs during REM sleep, the involvement of the LDT in penile erection was examined in unanesthetized head-restrained rats. To detect penile erection, corpus spongiosum of the penis (CSP) pressure was measured through a telemetric device with simultaneous bulbospongiosum (BS) muscle EMG recording through stainless wires. Electrical stimulation in and around the LDT induced the following three CSP pressure patterns: 1) a full erection pattern indistinguishable from the nonevoked or spontaneous erection, characterized by a slow increase in CSP pressure with additional sharp CSP peaks associated with BS muscle bursts, 2) a muscular pattern characterized by sharp CSP pressure peaks but in the absence of a vascular component, i.e., without an increase in baseline CSP pressure, and 3) a mixed-type response characterized by high-frequency CSP pressure peaks followed by a full erection response. Full erections were evoked in and around the LDT, including more medially and ventrally. The sites for inducing mixed-type events were intermingled with the sites that triggered full erections in the anterior half of the LDT, whereas they were separated in the posterior half. The sites for muscular responses were lateral to the sites for full erections. Finally, a CSP pressure response identical to micturition was evoked in and around the Barrington's nucleus and in the dorsal raphe nucleus. These results suggest that the LDT and surrounding region are involved in the regulation of penile erection. Moreover, different anatomical areas in the mesopontine tegmentum may have specific roles in the regulation of penile erection and micturition.

Suppressive effect of acupuncture stimulation to the sacral segment on the state of vigilance and the brainstem cholinergic neurons.

The effects of acupuncture stimulation to the sacral segment on the electroencephalogram (EEG) and activity of the cholinergic neurons in the laterodorsal tegmental nucleus (LDT) were examined in urethane-anesthetized rats. When EEG was small amplitude and higher frequency, the stimulation to the sacral segment induced large amplitude and slow EEG with latencies ranged from 45 sec to 12 min, and durations from 48 sec to 56 min. The stimulus induced EEG is composed of significant increase in delta power and significant decrease in theta and beta powers. Firing rate of the cholinergic LDT neurons significantly decreased from 2.9+/-1.5 Hz to 1.1+/-0.8 Hz after the stimulus (n=12, p<0.05). The decrease of neuronal activity always preceded to the start of large and slow EEG, while the increase of the activity always preceded to the change of EEG from large slow wave to small faster wave. These results suggest that the acupuncture stimulation to the sacral segment changes the state of the animals from light anesthesia to deep anesthesia, and that the change is mediated by the suppression of the cholinergic neurons in the LDT.

Tripartite relationship among P300, clinical features and brain structure in neuroleptic-naive schizophrenia.

Auditory P300 abnormalities in schizophrenia patients have been repeatedly reported by many studies. However, reported relationships among P300 abnormalities, clinical features and other biological variables, such as abnormalities in structural brain imaging, are notably discrepant. This is partially due to the inclusion of patients who have had long-term administration of neuroleptics and those from whom this treatment has been withdrawn. The present study measures event-related potentials in 13 neuroleptic-naive schizophrenia patients using an auditory oddball paradigm to clarify the relationships among P300 amplitude, clinical features and brain structure. All patients underwent computed tomography to estimate the area of the right and left frontal cortical sulci and Sylvian fissures. Clinical symptoms were assessed using the Positive And Negative Syndrome Scale. The high correlation coefficients were obtained between P300 amplitude and the anxiety/depression factor score (r = -0.77), the positive factor score (r = -0.58) and between P300 amplitude and the area ratios of the fronto-temporal region (r = -0.66). These findings show that fronto-temporal region and P300 amplitude are closely related to the earliest stage of illness even in neuroleptic-naive patients.

Activation of medial prefrontal cortex by phencyclidine is mediated via a hippocampo-prefrontal pathway.

Phencyclidine (PCP) is a psychotomimetic drug that elicits schizophrenia-like symptoms in healthy persons, and administration of PCP to animals is used as a pharmacological model of schizophrenia. We recently demonstrated that systemic administration of PCP to rats produces long-lasting activation of medial prefrontal cortex (mPFC) neurons with augmentation of locomotor activity, whereas direct application of PCP to mPFC neurons has little effect on their firing activity. These findings suggest that PCP-induced activation of mPFC neurons is elicited mainly via excitatory inputs from regions outside the mPFC. In the present study, we examined effects of local application of PCP to the ventral hippocampus (vHIP) on firing activity of PFC neurons in freely moving rats. PCP locally perfused into the vHIP increased spontaneous discharges of PFC neurons during perfusion with augmentation of locomotor activity. Local application of a more selective NMDA receptor antagonist, MK801, to vHIP neurons under anesthesia increased the spontaneous firing rates of most neurons directly projecting to the mPFC, whereas local application of MK801 to mPFC neurons did not induce excitatory responses in any of those neurons. The present results indicate that tonic excitatory inputs from the vHIP to the PFC may trigger development of behavioral abnormalities.

Different effects of phencyclidine and methamphetamine on firing activity of medial prefrontal cortex neurons in freely moving rats.

The purpose of this study was to compare the effects of systemically administered MAP with those of phencyclidine (PCP), both of which induced comparable locomotor activity, on firing activity of medial prefrontal cortex (mPFC) neurons in freely moving rats. The results show that, unlike PCP, acutely administered MAP produced little changes in firing activity of mPFC neurons.

Effects of acupuncture to the sacral segment on the bladder activity and electroencephalogram.

Using urethane-anaesthetized rats, the effects of acupunctural stimulation to the sacral segment on the urinary bladder activity and cortical electroencephalogram (EEG) were examined. The acupuncture suppressed urinary bladder activity in 36 of 68 trials. On many occasions (22/36 trials), suppression was accompanied by an increase in EEG amplitude. In such cases, the EEG power increased in all frequency bands after stimulation. The same EEG changes could be induced when the bladder was empty with no contraction. The results suggest that acupuncture stimulation affects both the bladder activity and sleep-arousal system.