Jingyi Ma

Relation between hippocampal γ waves and behavioral disturbances induced by phencyclidine and methamphetamine

The relationship between hippocampal electrical activity and behavioral hyperactivity induced by either phencyclidine (PCP) or methamphetamine (MAP) was examined in freely behaving rats. The EEGs at the hippocampal CA1 region were simultaneously recorded with the animals behavior for 2 h after administration of either PCP or MAP. PCP (10 mg/kg, intraperitoneal (i.p.)) significantly increased locomotor activity including rearing, walking, head-weaving and circling. Spectral analysis of the EEG showed that hippocampal gamma waves (30-70 Hz), but not other frequency bands, were significantly increased from 5 to 120 min after systemic injection of PCP. Inactivation of the medial septum with muscimol, a gamma-aminobutyric acid receptor A agonist, 15 min prior to injection of PCP, suppressed both hippocampal gamma waves and locomotor activity. MAP (1.5 mg/kg, i.p.) also increased locomotor activity for longer than 2 h. During the behavioral hyperactivity induced by MAP, hippocampal EEG showed θ and gamma rhythms that were not significantly different from those during walking before MAP. However, MAP-induced behavioral activity was suppressed by pre-injection of muscimol in the medial septum, which also decreased hippocampal gamma activity. It is suggested that the medial septum plays a role in mediating behavioral disturbances induced by both PCP and MAP through control of the hippocampal electrical activity, and that hippocampal gamma waves may play a permissible role in the expression of behaviors.

Involvement of the nucleus accumbens-ventral pallidal pathway in postictal behavior induced by a hippocampal afterdischarge in rats

The hypothesis that postictal motor behaviors induced by a hippocampal afterdischarge (AD) are mediated by a pathway through the nucleus accumbens (NAC) and ventral pallidum (VP) was evaluated in freely moving rats. Tetanic stimulation of the hippocampal CA1 evoked an AD of 15-30 s and an increase in number of wet-dog shakes, face washes, rearings and locomotor activity. Bilateral injection of haloperidol (5 micrograms/side) or the selective dopamine D2 receptor antagonist, (+/-)-sulpiride (200 ng/side) before the hippocampal AD, into the NAC selectively reduced rearings and locomotor activity, but not the number of wet-dog shakes and face washes. Injection of R(+)-SCH-23390 (1 microgram/side), a D1 receptor antagonist, or rimcazole (0.4 mg/side), a sigma opioid receptor antagonist, into the NAC did not significantly alter postictal behaviors. Bilateral injection of muscimol (1 ng/side), a gamma-aminobutyric acid (GABAA) receptor agonist, into the VP before the AD significantly blocked all postictal behaviors. It is concluded that postictal locomotor activity induced by a hippocampal AD is mediated by activation of dopamine D2 receptors in the NAC and a pathway through the VP.

Schizophrenia-like behavioral changes after partial hippocampal kindling.

The effect of hippocampal kindling on behavioral changes following 10 and 21 hippocampal afterdischarges (ADs) or electrographic seizures was examined in behaving rats. As compared to control, non-stimulated rats, 21 but not 10 hippocampal ADs resulted in a decrease in social contact, an increase in social isolation, and an increase in climbing and chasing behavior tested in an open field 3 days after cessation of kindling. Porsolt forced swimming test was not different among the control, 10- or 21-AD groups of rats. A deficit in sensorimotor gating, measured by prepulse inhibition of an acoustic startle, was observed in kindled as compared to control rats at 2 weeks after 21 ADs, but not after 10 ADs. Similarly, methamphetamine (1 mg/kg i.p.) induced higher locomotor activity in kindled rats, as compared to controls, after 21 ADs but not after 10 ADs. Spontaneous locomotor activity in a novel cage, without drug administration, was not different between kindled and control rats. These findings suggest that behavioral alterations after repeated hippocampal electrographic seizures may be mediated by increased dopaminergic functions, which may also mediate the psychiatric symptoms in human epileptic patients.

The medial septum mediates impairment of prepulse inhibition of acoustic startle induced by a hippocampal seizure or phencyclidine

The involvement of the septohippocampal system on the impaired sensorimotor gating induced by phencyclidine (PCP) or by an electrically induced hippocampal seizure was examined in behaving rats. An impaired sensorimotor gating, measured by prepulse inhibition (PPI) of the acoustic startle response, was observed following a hippocampal afterdischarge (AD) or systemic injection of PCP and was accompanied with an increase in hippocampal gamma waves (30-70 Hz). The medial septum infusion with muscimol (0.25 microg), a GABA(A) receptor agonist, 15 min prior to PCP or a hippocampal AD, prevented the impairment of sensorimotor gating and the increase in gamma waves. By itself, muscimol (0.25 microg) injection into the medial septum did not affect PPI, although it significantly suppressed spontaneous gamma waves. In order to identify subpopulations of neurons mediating the sensorimotor gating deficit and the hippocampal gamma wave increase, 0.14-0.21 microg of p75 antibody conjugated to saporin (192 IgG-saporin) was injected into the medial septum to selectively lesion the septohippocampal cholinergic neurons. Neither the PPI deficit nor the gamma wave increase induced by PCP or a hippocampal AD was affected by 192 IgG-saporin lesion of the medial septum. It is concluded that increase in neural activity in the medial septum participates in the impairment of sensorimotor gating and the increase in hippocampal gamma waves induced by PCP or a hippocampal AD. It is suggested that the GABAergic but not the cholinergic septohippocampal neurons mediate the sensorimotor gating deficit.

Limbic System Participates in Mediating the Effects of General Anesthetics

In a previous study, we reported that inactivation of the medial septum or the hippocampus by muscimol, a GABAA receptor agonist, potentiated the effects of a general anesthetic. In this study, we further investigated whether other structures that are connected to the septohippocampal system are involved in mediating general anesthesia. In freely behaving rats, muscimol (0.25 μg) or saline was infused intracerebrally into one of four areas—the supramammillary area (SUM), nucleus accumbens (NAC), ventral pallidum (VP), and ventral tegmental area (VTA)—and righting, pain, and EEG responses were recorded following either halothane or sodium pentobarbital, representing inhalational and injectable general anesthetic, respectively. The effect of halothane (2%) or pentobarbital (20 mg/kg i.p.) in abolishing the righting, pain response, or low-voltage neocortical activity was enhanced, and the initial behavioral hyperactivity (delirium) was reduced, after muscimol as compared to after saline infusion in SUM, NAC, VP, and VTA. EEGs in the hippocampus and the sensorimotor cortex following halothane or pentobarbital showed increased delta, and decreased hippocampal theta and gamma waves after muscimol infusion as compared to saline infusion in SUM, NAC, VP, and VTA. By contrast, infusion of muscimol in the median raphe increased locomotion and did not significantly alter the behavioral or EEG effects of halothane or pentobarbital. It is suggested that structures that activate the limbic cortices (MS, SUM, and VTA but not the median raphe) or mediate the output of the hippocampus (NAC and VP) normally participate in maintaining consciousness and inactivation of these structures potentiates the response to a general anesthetic.

Activation of immobility-related hippocampal theta by cholinergic septohippocampal neurons during vestibular stimulation.

The vestibular system has been suggested to participate in spatial navigation, a function ascribed to the hippocampus. Vestibular stimulation during spatial navigation activates a hippocampal theta rhythm (4–10 Hz), which may enhance spatial processing and motor response. We hypothesize that a cholinergic, atropine‐sensitive theta is generated during passive whole‐body rotation in freely behaving rats. Hippocampal EEGs were recorded by implanted electrodes in CA1 while rats were rotated on a vertical axis, for a minute or longer, at different angular velocities. Rotation induced a continuous hippocampal theta rhythm while the rat was immobile, in both light and dark conditions. Theta peak frequency showed a significant increase during high (50–70 rpm) as compared with a lower (20–49 rpm) rotational velocity. Rotation‐induced theta was abolished by muscarinic receptor antagonist atropine sulfate (50 mg/kg i.p.) but not by atropine methyl nitrate (50 mg/kg i.p.), which did not pass the blood‐brain barrier. Theta was attenuated in rats in which cholinergic neurons in the medial septum (MS) were lesioned with 192 IgG‐saporin (0.14 μg in 0.4 μl), as confirmed by depletion of MS cells immunoreactive to choline acetyltransferase and an absence of acetylcholinesterase staining in the hippocampus. Bilateral lesion of the vestibular receptors by sodium arsanilate (30 mg in 0.1 ml, intratympanically) also attenuated the rotation‐induced theta rhythm. In intact rats, field excitatory postsynaptic potentials (fEPSPs) in CA1 evoked by commissural stimulation were smaller during walking or rotation as compared with during immobility. Modulation of fEPSP was absent following atropine sulfate in intact rats and in 192 IgG‐saporin lesion rats. In summary, this is the first report of a continuous atropine‐sensitive hippocampal theta in the rat induced by vestibular stimulation during rotation, and accompanied by cholinergic modulation of hippocampal synaptic transmission. Vestibular‐activated septohippocampal cholinergic activity could be an important component in sensorimotor processing and spatial memory.

Brain areas that influence general anesthesia

This document reviews the literature on local brain manipulation of general anesthesia in animals, focusing on behavioral and electrographic effects related to hypnosis or loss of consciousness. Local inactivation or lesion of wake-active areas, such as locus coeruleus, dorsal raphe, pedunculopontine tegmental nucleus, perifornical area, tuberomammillary nucleus, ventral tegmental area and basal forebrain, enhanced general anesthesia. Anesthesia enhancement was shown as a delayed emergence (recovery of righting reflex) from anesthesia or a decrease in the minimal alveolar concentration that induced loss of righting. Local activation of various wake-active areas, including pontis oralis and centromedial thalamus, promoted behavioral or electrographic arousal during maintained anesthesia and facilitated emergence. Lesion of the sleep-active ventrolateral preoptic area resulted in increased wakefulness and decreased isoflurane sensitivity, but only for 6 days after lesion. Inactivation of any structure within limbic circuits involving the medial septum, hippocampus, nucleus accumbens, ventral pallidum, and ventral tegmental area, amygdala, entorhinal and piriform cortex delayed emergence from anesthesia, and often reduced anesthetic-induced behavioral excitation. In summary, the concept that anesthesia works on the sleep-wake system has received strong support from studies that inactivated/lesioned or activated wake-active areas, and weak support from studies that lesioned sleep-active areas. In addition to the conventional wake-sleep areas, limbic structures such as the medial septum, hippocampus and prefrontal cortex are also involved in the behavioral response to general anesthesia. We suggest that hypnosis during general anesthesia may result from disrupting the wake-active neuronal activities in multiple areas and suppressing an atropine-resistant cortical activation associated with movements.

Medial septum mediates the increase in post-ictal behaviors and hippocampal gamma waves after an electrically induced seizure

Hippocampal EEG and behavior of freely moving rats were studied before and after a hippocampal afterdischarge (AD), with or without reversible inactivation of the medial septum (MS) by muscimol. Muscimol suppressed the normal hippocampal EEG, including theta (5-10 Hz) and gamma (30-70 Hz) waves. After a hippocampal AD, hippocampal gamma waves were decreased for about 2 min and then increased at 3-10 min, while power of EEG of <30 Hz was decreased at </=3 min and showed no increase after an AD. Muscimol injection in the MS before the AD blocked the post-ictal increase of the gamma waves. In rats injected with vehicle in the MS, post-ictal increase in gamma waves was accompanied by an increase in horizontal locomotion, rearings, face washes, and wet dog shakes. In rats injected with muscimol in the MS before the AD, both the post-ictal increase in gamma waves and behaviors were completely suppressed. Muscimol injection in the MS after the AD significantly suppressed both gamma waves and post-ictal behaviors, as compared to vehicle-injected rats, but to a lesser degree than rats injected with muscimol in the MS before the AD. Hippocampal AD duration was not significantly affected by muscimol injection in the MS. We conclude that the MS is responsible for the maintenance of the normal and the post-ictal gamma waves. We suggest that the post-ictal gamma waves in the hippocampus may drive post-ictal behaviors, and in previous studies, we showed that this may occur through the nucleus accumbens.

Deep brain stimulation of the medial septum or nucleus accumbens alleviates psychosis-relevant behavior in ketamine-treated rats

Deep brain stimulation (DBS) has been shown to be effective for relief of Parkinsons disease, depression and obsessive-compulsive disorder in humans, but the effect of DBS on psychosis is largely unknown. In previous studies, we showed that inactivation of the medial septum or nucleus accumbens normalized the hyperactive and psychosis-related behaviors induced by psychoactive drugs. We hypothesized that DBS of the medial septum or nucleus accumbens normalizes the ketamine-induced abnormal behaviors and brain activity in freely moving rats. Male Long-Evans rats were subcutaneously injected with ketamine (3 mg/kg) alone, or given ketamine and DBS, or injected with saline alone. Subcutaneous injection of ketamine resulted in loss of gating of hippocampal auditory evoked potentials (AEPs), deficit in prepulse inhibition (PPI) and hyperlocomotion, accompanied by increased hippocampal gamma oscillations of 70-100 Hz. Continuous 130-Hz stimulation of the nucleus accumbens, or 100-Hz burst stimulation of the medial septum (1s on and 5s off) significantly attenuated ketamine-induced PPI deficit and hyperlocomotion. Medial septal stimulation also prevented the loss of gating of hippocampal AEPs and the increase in hippocampal gamma waves induced by ketamine. Neither septal or accumbens DBS alone without ketamine injection affected spontaneous locomotion or PPI. The results suggest that DBS of the medial septum or nucleus accumbens may be an effective method to alleviate psychiatric symptoms of schizophrenia. The effect of medial septal DBS in suppressing both hippocampal gamma oscillations and abnormal behaviors induced by ketamine suggests that hippocampal gamma oscillations are a correlate of disrupted behaviors.

Altered neurotrophin receptor function in the developing prefrontal cortex leads to adult-onset dopaminergic hyperresponsivity and impaired prepulse inhibition of acoustic startle

BACKGROUND Survival and differentiation of neurons and the formation and maintenance of synapses in the cerebral cortex may be affected in schizophrenia. Since neurotrophins play an important role in these events, behavioral effects relevant to schizophrenia were investigated in rats that had compromised neurotrophin function during prefrontal cortical development. METHODS Neonatal rat pups were injected into the developing prefrontal cortex with a depot preparation of p75 receptor antibody conjugated to saporin. Animals were tested for dopaminergic hyperresponsivity and prepulse inhibition of acoustic startle at 5 or 10 weeks. Neonatal and adult brain sections were examined for morphologic abnormality. RESULTS Animals that received neonatal injections of p75 antibody conjugated to saporin showed significantly increased amphetamine-induced locomotion and rearing and impairment of prepulse inhibition of acoustic startle at 10 weeks of age but not at 5 weeks. Examination of adult brain sections revealed apparently normal structure, whereas neonatal brain sections showed apoptotic cells in the developing prefrontal cortex in pups that received p75 antibody conjugated to saporin. CONCLUSIONS Compromised p75 neurotrophin receptor function in the developing prefrontal cortex may be associated with the manifestation of adult-onset dopaminergic hyperresponsivity and impaired prepulse inhibition and therefore may be involved in the pathogenesis of schizophrenia.