Dopamine D1 receptors are responsible for stress-induced emotional memory deficit in mice.

It is established that stress impairs spatial learning and memory via the hypothalamus-pituitary-adrenal axis response. Dopamine D1 receptors were also shown to be responsible for a stress-induced deficit of working memory. However, whether stress affects the subsequent emotional learning and memory is not elucidated yet. Here, we employed the well-established one-trial step-through task to study the effect of an acute psychological stress (induced by tail hanging for 5, 10, or 20 min) on emotional learning and memory, and the possible mechanisms as well. We demonstrated that tail hanging induced an obvious stress response. Either an acute tail-hanging stress or a single dose of intraperitoneally injected dopamine D1 receptor antagonist (SCH23390) significantly decreased the step-through latency in the one-trial step-through task. However, SCH23390 prevented the acute tail-hanging stress-induced decrease in the step-through latency. In addition, the effects of tail-hanging stress and/or SCH23390 on the changes in step-through latency were not through non-memory factors such as nociceptive perception and motor function. Our data indicate that the hyperactivation of dopamine D1 receptors mediated the stress-induced deficit of emotional learning and memory. This study may have clinical significance given that psychological stress is considered to play a role in susceptibility to some mental diseases such as depression and post-traumatic stress disorder.

[Hippocampal-prefrontal cortical circuit and working memory].

The study on learning and memory is one of the striking subjects in neuroscience today. In the cerebral cortex, it is has been proved that, the hippocampus, the prefrontal cortex and the hippocampal-prefrontal cortical circuit are important to working memory. In this paper, we review findings of the anatomical and electrophysiological characteristics of the hippocampal-prefrontal cortical circuit and the roles of these three structures in working memory.

The effects of centrally administered fluorocitrate via inhibiting glial cells on working memory in rats.

Although prefrontal and hippocampal neurons are critical for spatial working memory, the function of glial cells in spatial working memory remains uncertain. In this study we investigated the function of glial cells in rats' working memory. The glial cells of rat brain were inhibited by intracerebroventricular (icv) injection of fluorocitrate (FC). The effects of FC on the glial cells were examined by using electroencephalogram (EEG) recordings and delayed spatial alternation tasks. After icv injection of 10 microL of 0.5 nmol/L or 5 nmol/L FC, the EEG power spectrum recorded from the hippocampus increased, but the power spectrum for the prefrontal cortex did not change, and working memory was unaffected. Following an icv injection of 10 microL of 20 nmol/L FC, the EEG power spectra in both the prefrontal cortex and the hippocampus increased, and working memory improved. The icv injection of 10 microL of 50 nmol/L FC, the EEG power spectra in both the prefrontal cortex and in the hippocampus decreased, and working memory was impaired. These results suggest that spatial working memory is affected by centrally administered FC, but only if there are changes in the EEG power spectrum in the prefrontal cortex. Presumably, the prefrontal glial cells relate to the working memory.

Reversible disconnection of the hippocampal-prelimbic cortical circuit impairs spatial learning but not passive avoidance learning in rats.

Wistar rats, treated with the GABA(A) receptor agonist muscimol, were used to investigate the role of the hippocampal-prelimbic cortical (Hip-PLC) circuit in spatial learning in the Morris water maze task, and in passive avoidance learning in the step-through task. In the water maze task, animals were trained for three consecutive days and tested 24 h after the end of training. In the step-through task, the animals were trained once and tested 24h after training. On the training days, daily infusion of muscimol (0.5 microg/0.25 microl) was given (1) bilaterally to the ventral hippocampus (vHip), (2) bilaterally to the prelimbic cortex (PLC), (3) to the unilateral vHip and the ipsilateral PLC, or (4) for disconnecting the Hip-PLC circuit, to both the unilateral vHip and the contralateral PLC 30 min before training. The results showed that inhibition of the vHip resulted in disruption of performance in both tasks. Inhibition of the PLC produced impaired water maze performance, but had no effect on the step-through task. Disconnection of the Hip-PLC circuit produced similar effects to PLC inhibition. However, simultaneous inhibition of the unilateral vHip and the ipsilateral PLC had little effect on performance of the water maze task. The results suggested that spatial learning depends on the Hip-PLC circuit, whereas passive avoidance learning is independent of this circuit.

Neonatal tactile stimulation enhances spatial working memory, prefrontal long-term potentiation, and D1 receptor activation in adult rats.

Environmental stimuli during neonatal periods play an important role in the development of cognitive function. In this study, we examined the long-term effects of neonatal tactile stimulation (TS) on spatial working memory (SWM) and related mechanisms. We also investigated whether TS-induced effects could be counteracted by repeated short periods of maternal separation (MS). Wistar rat pups submitted to TS were handled and marked transiently per day during postnatal days 2-9 or 10-17. TS/MS pups were stimulated in the same way as TS pups and then individually separated from their mother for 1h/day. Their nontactile stimulated (NTS) siblings served as controls. In adulthood, TS and TS/MS rats showed better performance in two versions of the delayed alternation task and superior in vivo long-term potentiation of the hippocampo-prefrontal cortical pathway when compared with controls. Furthermore, there were more doses of A77636 (a selective dopamine D1 agonist) to significantly improve SWM performance in TS and TS/MS rats than in NTS rats, suggesting that activation of prefrontal D1 receptors in TS and TS/MS rats is more optimal for SWM function than in NTS rats. MS did not counteract TS-induced effects because no significant difference was found between TS/MS and TS animals. These data indicate that in early life, external tactile stimulation leads to long-term facilitative effects in SWM-related neural function.

Disconnection of the hippocampal-prefrontal cortical circuits impairs spatial working memory performance in rats.

There is a unidirectional, ipsilateral and monosynaptic projection from the hippocampus to the prefrontal cortex. The cognitive function of hippocampal-prefrontal cortical circuit is not well established. In this paper, we use muscimol treated rats to investigate the roles of the hippocampal-prefrontal cortical circuits in spatial working memory, as assessed with a delayed spatial alternation task. First of all, the effect of muscimol on EEG power of infusion area was observed for confirmation of the dosage of muscimol to inhibit the function of infusion area. The results show that the EEG power of the ventral hippocampus and the prelimbic area of the prefrontal cortex were inhibited by local infusion of muscimol (0.5 microg in 0.25 microl PBS) into the above areas, respectively. Delayed alternation performance was significantly impaired when muscimol at this dosage was infused (1) bilaterally into the ventral hippocampus, (2) bilaterally into the prelimbic area, (3) unilaterally into the ventral hippocampus and simultaneously contralaterally into the prelimbic area. Infusion of muscimol either unilaterally into the ventral hippocampus or unilaterally into the prelimbic area did not impair delayed alternation performance. The present results suggest that any structures in this circuit is damaged or inhibited bilaterally, the spatial working memory will be disrupted. It means the hippocampal-prefrontal cortical circuit plays an important role in spatial working memory.

The in vivo synaptic plasticity mechanism of EGb 761-induced enhancement of spatial learning and memory in aged rats.

It has not been uniform to date that the Ginkgo biloba extracts enhance cognitive function in aged animals, and the mechanisms of action remain difficult to elucidate. In this study, the Morris water maze task and electrophysiological methods were used to study the effects of repeated daily administration of EGb 761, a standardized extract from G. biloba leaves, on hippocampal-dependent spatial learning and memory and synaptic plasticity of aged rats. The adult subjects perform the Morris water maze task better than aged rats, as a cellular mechanism, the hippocampal long-term potentiation (LTP) elicited from adult animals is robust (139.29+/-2.7%). In addition, the spatial learning and memory of aged rats that had been fed on an EGb 761-supplemented diet (60 mg kg(-1)) for 30 days were significantly better than those of control aged rats. The magnitude of LTP (116.63+/-3.6%) recorded in vivo from the hippocampus CA1 area of aged rats was significantly enhanced by EGb 761 (60 mg kg(-1)). In conclusion, the spatial learning and memory of aged rats is worse than that of young subjects, and EGb 761, acting as a 'cognitive enhancer', has benefit on synaptic plasticity and cognition in aged rats. The present data further confirmed that enhancement of synaptic plasticity of the hippocampus might ameliorate the deficit in spatial learning and memory in aged rats.

Aniracetam attenuates H2O2-induced deficiency of neuron viability, mitochondria potential and hippocampal long-term potentiation of mice in vitro.

Objective It is known that free radicals are involved in neurodegeneration and cognitive dysfunction, as seen in Alzheimer' s disease (AD) and aging. The present study examines the protective effects of aniracetam against H2O2-induced toxicity to neuron viability, mitochondria potential and hippocampal long-term potentiation (LTP). Methods Tetrazolium salt 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) was used to detect neuronal viability. MitoTracker Red (CMX Ros), a fluorescent stain for mitochondria, was used to measure mitochondria potential. Electrophysiological technique was carried out to record hippocampal LTP. Results H2O2 exposure impaired the viability of neurons, reduced mitochondria potential, and decreased LTP in the CA1 region of hippocampus. These deficient effects were significantly rescued by pre-treatment with aniracetam (10-100 mu mol/L). Conclusion These results indicate that aniracetam has a strong neuroprotective effect against H2O2-induced toxicity, which could partly explain the mechanism of its clinical application in neurodegenerative diseases.

Extract of Ginkgo biloba leaves reverses yohimbine-induced spatial working memory deficit in rats.

Extract of Ginkgo biloba is used to alleviate age-related decline in cognitive function, which may be associated with the loss of catecholamines in the prefrontal cortex. The purpose of this study was to verify whether alpha-2 adrenergic activity is involved in the facilitative effects of extract of Ginkgo biloba on prefrontal cognitive function. Male Wistar rats were trained to reach criterion in the delayed alternation task (0, 25, and 50-s delay intervals). A pilot study found that 3 or 4 mg/kg of yohimbine (intraperitoneal) reduced the choice accuracy of the delayed alternation task in a dose and delay-dependent manner, without influencing motor ability or perseverative behaviour. Acute oral pre-treatment with doses of 50, 100, or 200 mg/kg (but not 25 mg/kg) of extract of Ginkgo biloba prevented the reduction in choice accuracy induced by 4 mg/kg yohimbine. These data suggest that the prefrontal cognition-enhancing effects of extract of Ginkgo biloba are related to its actions on alpha-2-adrenoceptors.

Age-related effects of bromocriptine on sensory gating in rhesus monkeys.

Declines in dopamine neurotransmission are a robust characteristic of the process of normal aging. Using neuroimaging, biochemical and cognitive methods, age-related reduction of D2 receptor has been noted in a wide range of species. On the other hand, it is well known that dopamine plays a crucial role in the modulation of sensory gating. Here, we examined age-related alterations of D2 receptor in rhesus monkeys, using a sensory gating paradigm. The direct D2 receptor agonist, bromocriptine, was characterized in young adult and aged monkeys. We found bromocriptine disrupted sensory gating in young adult monkeys but not in aged ones. Our results provided new evidence that there is a functional decline of D2 receptor in aged monkeys.

Effects of ginkgo biloba extract on cation currents in rat ventricular myocytes.

Ginkgo biloba extract (GBE), a valuable natural product for cerebral and cardiovascular diseases, is mainly composed of two classes of constituents: terpene lactones (e.g., ginkgolide A and B, bilobalide) and flavone glycosides (e.g., quercetin and kaempferol). Its electrophysiological action in heart is yet unclear. In the present study, using whole-cell patch clamp technique, we investigated electrophysiological effects of GBE on cation channel currents in ventricular myocytes isolated from rat hearts. We found that GBE 0.01-0.1% inhibited significantly the sodium current (I(Na)), L-type calcium current (I(Ca)) and transient outward potassium current (IK(to)) in a concentration-dependent manner. Surprisingly, its main ingredients, ginkgolide A (GB A), ginkgolide B (GB B) and bilobalide (GB BA) at 0.1 mM did not exhibit any significant effect on these cation channel currents. These results suggested that GBE is a potent non-selective cation channel modulator in cardiaomyocytes. Other constituents (rather than GB A, GB B and GB BA) might be responsible for the observed inhibitory effects of GBE on cation channels.

Stress enables synaptic depression in CA1 synapses by acute and chronic morphine: possible mechanisms for corticosterone on opiate addiction.

The hippocampus, being sensitive to stress and glucocorticoids, plays significant roles in certain types of learning and memory. Therefore, the hippocampus is probably involved in the increasing drug use, drug seeking, and relapse caused by stress. We have studied the effect of stress with morphine on synaptic plasticity in the CA1 region of the hippocampus in vivo and on a delayed-escape paradigm of the Morris water maze. Our results reveal that acute stress enables long-term depression (LTD) induction by low-frequency stimulation (LFS) but acute morphine causes synaptic potentiation. Remarkably, exposure to an acute stressor reverses the effect of morphine from synaptic potentiation (approximately 20%) to synaptic depression (approximately 40%), precluding further LTD induction by LFS. The synaptic depression caused by stress with morphine is blocked either by the glucocorticoid receptor antagonist RU38486 or by the NMDA-receptor antagonist D-APV. Chronic morphine attenuates the ability of acute morphine to cause synaptic potentiation, and stress to enable LTD induction, but not the ability of stress in tandem with morphine to cause synaptic depression. Furthermore, corticosterone with morphine during the initial phase of drug use promotes later delayed-escape behavior, as indicated by the morphine-reinforced longer latencies to escape, leading to persistent morphine-seeking after withdrawal. These results suggest that hippocampal synaptic plasticity may play a significant role in the effects of stress or glucocorticoids on opiate addiction.

Effects of aniracetam on extracellular levels of transmitter amino acids in the hippocampus of the conscious gerbils: an intracranial microdialysis study.

The effects of aniracetam on extracellular amino acid levels in the hippocampus of conscious gerbils, with or without transient cerebral ischemia/reperfusion, were measured by microdialysis and reverse phase-high performance liquid chromatography. Increased extracellular levels of aspartate and glutamate that were observed in the hippocampus of conscious gerbils during transient global forebrain ischemia were reversed by aniracetam. In contrast, the level of extracellular gamma-aminobutyric acid was increased, while taurine was maintained at a higher level than other amino acids by administration of aniracetam (100 mg/kg, p.o.) 60 min before ischemia. Further, in contrast to ischemic animals, administration of aniracetam (100 mg/kg, p.o.) enhanced the release of glutamate and aspartate in the normal gerbil hippocampus. The results suggest that these effects might be due to a partial calcium agonist activity of aniracetam, and that the effects of aniracetam on amino acid levels might be a mechanism of protection against delayed neuronal death in the ischemic hippocampus, thereby improving memory dysfunction induced by ischemia/reperfusion.

Differential amplitude modulation of auditory evoked cortical potentials associated with brain state in the freely moving rhesus monkey.

We simultaneously recorded auditory evoked potentials (AEP) from the temporal cortex (TCx), the dorsolateral prefrontal cortex (dPFCx) and the parietal cortex (PCx) in the freely moving rhesus monkey to investigate state-dependent changes of the AEP. AEPs obtained during passive wakefulness, active wakefulness (AW), slow wave sleep and rapid-eye-movement sleep (REM) were compared. Results showed that AEP from all three cerebral areas were modulated by brain states. However, the amplitude of AEP from dPFCx and PCx significantly appeared greater attenuation than that from the TCx during AW and REM. These results indicate that the modulation of brain state on AEP from all three cerebral areas investigated is not uniform, which suggests that different cerebral areas have differential functional contributions during sleep-wake cycle.