Presynaptic muscarinic cholinergic receptors in the dorsal hippocampus regulate behavioral inhibition of preweanling rats

The aim of this research was to determine whether early maturation of the dorsal hippocampal cholinergic system mediates behavior exhibited by preweanling rats in the presence or absence of an unfamiliar adult male rat, a threatening stimulus. The behavioral responses that were examined included behavioral inhibition or freezing which emerges at 2 weeks of age and ultrasonic vocalizations. Prior to behavioral testing, oxotremorine, an M2 muscarinic receptor agonist that reduces cholinergic release from presynaptic terminals, was infused into the dorsal hippocampal dentate gyrus. Results demonstrated that 14-day-old rats with bilateral hippocampal infusions of a 1 microgram dose of oxotremorine exhibited significant deficits in freezing when exposed to the adult male rat. Importantly, oxotremorine had no significant effects on ultrasound emission and ambulatory activity when rat pups were tested in social isolation. Thus, effects of oxotremorine in the hippocampal dentate gyrus do not produce global changes in behavior. Results suggest that cholinergic release into the dorsal hippocampus facilitates the display of behavioral inhibition at the end of the second postnatal week. Behavioral deficits in freezing may reflect an oxotremorine-induced disruption of hippocampal cholinergic function underlying the processing of biologically relevant olfactory stimuli as well as mechanisms associated with attention.     

Presynaptic modulation of cholecystokinin release by protein kinase C in the rat hippocampus

The role of protein kinase C (PKC) in modulating the release of the octapeptide cholecystokinin (CCK-8) was investigated in rat hippocampal nerve terminals (synaptosomes). The PKC-activating phorbol ester 4beta-phorbol 12,13-dibutyrate (beta-PDBu) dose dependently (5-5,000 nM) increased CCK-8 release in a strictly Ca2+dependent way. This effect was observed only when synaptosomes were stimulated with the K+(A) channel blocker 4-aminopyridine (4-AP; 1 mM) but not with KCl (10-30 mM). The PDBu-induced exocytosis of CCK-8 was completely blocked by the two selective PKC inhibitors chelerythrine and calphostin-C and was not mimicked by alpha-PDBu, an inactive phorbol ester. In addition, an analogue of the endogenous PKC activator diacylglycerol, oleoylacetylglycerol, dose dependently increased CCK-8 exocytosis. Beta-PDBu (50-100 nM) also stimulated the 4-AP-evoked Ca2+-dependent release of the classic transmitter GABA, which co-localizes with CCK-8 in hippocampal interneurons. As a possible physiological trigger for PKC activation, the role of the metabotropic glutamate receptor was investigated. However, the broad receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid did not stimulate, but instead inhibited, both the CCK-8 and the GABA exocytosis. In conclusion, presynaptic PKC may stimulate exocytosis of distinct types of co-localizing neurotransmitters via modulation of presynaptic K+ channels in rat hippocampus.     

Presynaptic modulation of synaptic transmission and plasticity by brain-derived neurotrophic factor in the developing hippocampus

In addition to the regulation of neuronal survival and differentiation, neurotrophins may play a role in synapse development and plasticity. Application of brain-derived neurotrophic factor (BDNF) promotes long-term potentiation (LTP) in CA1 synapses of neonatal hippocampus, which otherwise exhibit only short-term potentiation. This is attributable, at least in part, to an attenuation of the synaptic fatigue induced by high-frequency stimulation (HFS). However, the prevention of synaptic fatigue by BDNF could be mediated by an attenuation of synaptic vesicle depletion from presynaptic terminals and/or a reduction of the desensitization of postsynaptic receptors. Here we provide evidence supporting a presynaptic effect of BDNF. The effect of BDNF on synaptic fatigue depended on the stimulation frequency, not on the stimulus duration nor on the number of stimulation pulses. BDNF was only effective when the synapses were stimulated at frequencies >50 Hz. Treatment with BDNF also potentiated paired-pulse facilitation (PPF), a parameter reflecting changes in the properties of presynaptic terminals. This effect of BDNF was restricted only to PPF elicited with interpulse intervals 相似文献   

Kainate receptors presynaptically downregulate GABAergic inhibition in the rat hippocampus

Using microcultured neurons and hippocampal slices, we found that under conditions that completely block AMPA receptors, kainate induces a reduction in the effectiveness of GABAergic synaptic inhibition. Evoked inhibitory postsynaptic currents (IPSCs) were decreased by kainate by up to 90%, showing a bell-shaped dose-response curve similar to that of native kainate-selective receptors. The down-regulation of GABAergic inhibition was not affected by antagonism of metabotropic receptors, while it was attenuated by CNQX. Kainate increased synaptic failures and reduced the frequency of miniature IPSCs, indicating a presynaptic locus of action. In vivo experiments using brain dialysis demonstrated that kainate reversibly abolished recurrent inhibition and induced an epileptic-like electroencephalogram (EEG) activity. These results indicate that kainate receptor activation down-regulates GABAergic inhibition by modulating the reliability of GABA synapses.     

Facilitation of feedback inhibition through blockade of glucocorticoid receptors in the hippocampus

In the present study the effects of intracerebroventricular (i.c.v.) and intrahippocampal administration of corticosteroid antagonists on basal hypothalamic-pituitary-adrenal (HPA) activity around the diurnal peak were compared in male Wistar rats. In two separate experiments the glucocorticoid receptor (GR) antagonist RU 38486 and the mineralocorticoid receptor (MR) antagonist RU 28318 were tested. One hour after GR antagonist injection, significant increases in plasma ACTH and corticosterone levels were observed in the i.c.v. treated rats, when compared to vehicle. In contrast, a significant decrease in ACTH levels, and a slight, but non-significant decrease in corticosterone concentrations were attained one hour after intrahippocampal injection of the GR antagonist. Injection of the MR antagonist, on the other hand, resulted in enhanced ACTH and corticosterone levels irrespective of the site of injection. These findings suggest that negative feedback inhibition at the circadian peak involves hippocampal MRs and extrahippocampal (hypothalamic) GRs. The latter feedback inhibition overrides a positive feedback influence exerted by endogenous corticosteroids through hippocampal GRs.     

Enhancement of latent inhibition in rats with electrolytic lesions of the hippocampus.

Two groups of rats—1 with electrolytic lesions of the hippocampus and 1 consisting of sham-operated controls—received flavor-aversion conditioning with 2 flavors. All subjects had received prior nonreinforced exposure to Flavor A. Latent inhibition was apparent in slower acquisition of the aversion to Flavor A than to Flavor B. Hippocampal lesions had no effect on acquisition to the nonpreexposed Flavor B but produced a marked enhancement of the latent inhibition effect. The contrast between this result and previous findings of an attenuation of latent inhibition in subjects with hippocampal lesions is discussed (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Ontogenesis of presynaptic GABAB receptor-mediated inhibition in the CA3 region of the rat hippocampus

gamma-Aminobutyric acid-B(GABAB) receptor-dependent and -independent components of paired-pulse depression (PPD) were investigated in the rat CA3 hippocampal region. Intracellular and whole cell recordings of CA3 pyramidal neurons were performed on hippocampal slices obtained from neonatal (5-7 day old) and adult (27-34 day old) rats. Electrical stimulation in the hilus evoked monosynaptic GABAA postsynaptic currents (eIPSCs) isolated in the presence of the ionotropic glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM) and D(-)2-amino-5-phosphovaleric acid (-AP5, 50 microM) with 2(triethylamino)-N-(2,6-dimethylphenyl) acetamine (QX314) filled electrodes. In adult CA3 pyramidal neurons, when a pair of identical stimuli was applied at interstimulus intervals (ISIs) ranging from 50 to 1,500 ms the amplitude of the second eIPSC was depressed when compared with the first eIPSC. This paired-pulse depression (PPD) was partially blocked by P-3-aminoprophyl -P-diethoxymethylphosphoric acid (CGP35348, 0.5 mM), a selective GABAB receptor antagonist. In neonates, PPD was restricted to ISIs shorter than 200 ms and was not affected by CGP35348. The GABAB receptor agonist baclofen reduced the amplitude of eIPSCs in a dose-dependent manner with the same efficiency in both adults and neonates. Increasing the probability of transmitter release with high Ca2+ (4 mM)/low Mg2+ (0.3 mM) external solution revealed PPD in neonatal CA3 pyramidal neurons that was 1) partially prevented by CGP35348, 2) independent of the membrane holding potential of the recorded cell, and 3) not resulting from a change in the reversal potential of GABAA eIPSCs. In adults the GABA uptake blocker tiagabine (20 microM) increased the duration of eIPSCs and the magnitude of GABAB receptor-dependent PPD. In neonates, tiagabine also increased duration of eIPSCs but to a lesser extent than in adult and did not reveal a GABAB receptor-dependent PPD. These results demonstrate that although GABAB receptor-dependent and -independent mechanisms of presynaptic inhibition are present onGABAergic terminals and functional, they do not operate at the level of monosynaptic GABAergic synaptic transmission at early stages of development. Absence of presynaptic autoinhibition of GABA release seems to be due to the small amount of transmitter that can access presynaptic regulatory sites.     

Role of the hippocampus in blocking and conditioned inhibition of the rabbit's nictitating membrane response.

In Exp I, bilateral aspiration of the dorsal hippocampus produced a disruption of blocking of 30 New Zealand rabbits' nictitating membrane response in L. J. Kamin's (1968, 1969) 2-stage paradigm, but had no effect on the formation of a Pavlovian conditioned inhibitor in Exp II (27 Ss). Results of Exp I indicate that normal Ss and those with cortical lesions given conditioning to a light-plus-tone CS gave CRs to both light and tone during nonreinforced presentations of each (test phase). If, however, compound conditioning was preceded by tone acquisition, only the tone elicited a CR during testing; that is, blocking was observed. In Ss with hippocampal lesions, however, CRs were given to both light and tone during testing whether or not compound conditioning was preceded by tone acquisition. Data from Exp II show that Ss with hippocampal lesions could discriminate as well as normal Ss and those with cortical lesions between a light (CS+) and light plus tone (CS-). In addition, when the inhibitory tone was subsequently paired with the UCS in retardation testing, Ss in all 3 lesion conditions acquired the CR at the same rate. Thus, it appears that hippocampal lesions do not disrupt conditioned inhibition. Results are taken as support for the view that the hippocampus is responsible for "tuning out" stimuli that have no adaptive value to the organism. (27 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Hydroxylamine blocks adenosine A1 receptor-mediated inhibition of synaptic transmission in rat hippocampus

BACKGROUND AND PURPOSE: Stroke-induced hemiparesis involving the arm and hand results in regular, repeated overuse of the opposite hand and wrist. Because repetitive hand and wrist movement is a common cause of carpal tunnel syndrome (CTS), we examined the nonparetic upper limb in stroke patients for evidence of CTS. METHODS: We measured bilaterally sensory nerve conduction velocity (SNCV), motor nerve conduction velocity (MNCV), sensory nerve action potentials (SNAP) at the wrist, palm-to-wrist distal sensory latency (DSL), palm-to-wrist SNAP, compound motor action potentials (CMAP), and distal motor latency (DML) in stroke patients and control subjects. Controls were right-handed, >/=65 years old, lucid, independent in their activities of daily living, and had no disease known to cause CTS. Stroke patients were divided into a functioning hand group (n=61) and a disused hand group (n=71). All patients had hemiplegia. RESULTS: Tinel's sign was observed on the nonparetic side in 57.7% of patients with a disused hand and in 31.1% of those with a functioning hand. All electrophysiological indices were significantly more abnormal on the nonparetic side than on the hemiparetic side or in controls. Patients with a disused hand showed greater abnormality on the nonparetic side in SNCV, SNAP, palm-to-wrist DSL, DML, and CMAP than patients with a functioning hand. CONCLUSIONS: Overuse of the nonparetic hand and wrist of the nonparetic side may result in CTS in stroke patients, especially when the paretic hand is not functional. Wrist splinting or other prophylactic treatments beginning soon after stroke might help to prevent CTS.     

Presynaptic potassium channels

The past year has witnessed some significant improvements in our understanding of the molecular diversity, subunit composition, and functional properties of K+ channels in heterologous expression systems. Immunocytochemical studies have yielded important information on the localization of K+ channel proteins to synaptic terminals in mammalian brain. Although a coherent picture of native presynaptic K+ channels' function in the mammalian central nervous system is not yet available, it may emerge from improvements in patch-clamp techniques and new applications of targeted knock-out technologies.     

Presynaptic function during muscle remodeling in insect metamorphosis

During metamorphosis the leg neuromuscular system of the moth Manduca sexta undergoes an extensive remodeling as the larval muscles degenerate and are replaced by new muscles in the adult. The terminal processes of persistent leg motoneurons undergo severe regression followed by regrowth (Consoulas et al., 1996), accompanied, as shown here, by the loss and re-establishment of functional presynaptic specializations. Before and shortly after the degeneration of the larval muscle, immunoreactivity for the vesicular protein synaptotagmin was localized to the presynaptic varicosities of the motoneurons. Similarly localized were distinct sites of Ca2+-dependent uptake of the fluorescent dye FM1-43. During myoblast migration and accumulation about the re-expanding motor axons, synaptotagmin immunoreactivity was widely distributed in axons, and specific FM1-43 staining revealed vesicle exocytosis in distal axon branches. During myoblast proliferation and fusion, and myotube formation, synaptotagmin staining remained widely distributed in nerve branches, whereas FM1-43 staining was more localized to subdomains of these nerve branches. These initial presynaptic active sites were transient and were replaced by new sites in more distal nerve processes as the muscle anlage increased in size and additional myotubes formed. After myotube separation, synaptotagmin staining disappeared from primary branches but remained distributed within secondary and high-order nerve branches. FM1-43 staining was detected in high-order branches only. During muscle fiber striation, growth, and maturation, both FM1-43 staining and synaptotagmin immunoreactivity became localized to terminal varicosities. Thus, presynaptic function can persist after the loss of the target and occurs transiently in axon shafts before becoming restricted to terminal domains as the underlying muscle fibers mature.     

Lamellar organisation in the rat hippocampus

A series of experiments was conducted in the urethane anaesthetised rat to determine the organisation of some hippocampal pathways in this species, using stimulating and recording microelectrodes to elicit and record pupulation spikes. It was found that the mossy fibres, alvear fibres and perforant path were clearly arranged in a lamellar fashion. Lamellar organisation could not be demonstrated for the afferents in the stratum radiatum which include the Schaffer collaterals. It was concluded that hippocampal organisation in this species essentially resembles that in the rabbit and cat.     

Ibotenate lesions of the hippocampus enhance latent inhibition in conditioned taste aversion and increase resistance to extinction in conditioned taste preference.

In 2 experiments, the effects of axon-sparing lesions of the hippocampus on performance in aversive and appetitive taste conditioning tasks were investigated. In Exp 1, hippocampally lesioned rats showed no impairment of conditioned taste aversion learning relative to controls, but they did display an increased sensitivity to latent inhibition (LI). In Exp 2, the same hippocampectomized rats acquired a conditioned taste preference but failed to show any evidence of extinction. The influence of the neurotoxic lesion on LI is in the opposite direction to the effect typically found following hippocampal damage induced by traditional methods. Accordingly, the data present challenges for most current theories of hippocampal function. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Modulation of behavioral inhibition in appetitive extinction following manipulation of adrenal steroids in rats: Implications for involvement of the hippocampus.

Two experiments were conducted in this study, utilizing 57 male Sprague-Dawley rats. Exp I investigated the functional behavioral significance of the hormone-brain interaction in the extinction of an appetitive runway response in normal Ss and in those with lesions of the hippocampus. During extinction, half of the Ss in each group were given daily sc injections of corticosterone. While the classical retardation effect of hippocampal lesions on appetitive extinction was replicated, hormone treatment was without effect in normal or hippocampally damaged Ss. The absence of a hormone effect in normals was primarily attributed to a saturated limited-binding system operating in the normal S. Exp II tested this notion, repeating the 1st experiment, with adrenalectomized (ADX), ADX?+?corticosterone replacement, and normal groups of Ss. Adrenalectomy produced a striking facilitation of extinction, which was speculated to be the result of hyperactive inhibitory neural organ free from an inhibitory endocrine feedback. This was supported when corticosterone treatment normalized the progress of extinction in ADX Ss. (40 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neurogenesis in the adult human hippocampus

The genesis of new cells, including neurons, in the adult human brain has not yet been demonstrated. This study was undertaken to investigate whether neurogenesis occurs in the adult human brain, in regions previously identified as neurogenic in adult rodents and monkeys. Human brain tissue was obtained postmortem from patients who had been treated with the thymidine analog, bromodeoxyuridine (BrdU), that labels DNA during the S phase. Using immunofluorescent labeling for BrdU and for one of the neuronal markers, NeuN, calbindin or neuron specific enolase (NSE), we demonstrate that new neurons, as defined by these markers, are generated from dividing progenitor cells in the dentate gyrus of adult humans. Our results further indicate that the human hippocampus retains its ability to generate neurons throughout life.     

Memory beyond the hippocampus

Cultured hepatocytes of silver eel actively secreted only chylomicron-like lipoprotein. The rate of secretion per mg cellular protein per 24 hr was 2.2 times higher compared with that by yellow eel hepatocytes. Silver eel hepatocytes secreted lipids 2.5 times higher through the lipoprotein than yellow eel hepatocytes. Main lipid was triacylglycerol in either secreted lipoprotein and composition of apolipoproteins of both secreted lipoproteins was the same. The incorporation of 3H-leucine into the lipoprotein secreted by silver eel hepatocytes was 2.4 times higher, but that of 14C-acetate was not significantly different. Protein and lipids composition of plasma lipoproteins of silver eel was significantly higher and lower compared with those of yellow eel, respectively. We suggest that the secreted lipoprotein of silver eel hepatocytes transport much more lipids to other tissues than that of yellow eel hepatocytes.     

Stress: metaplastic effects in the hippocampus

Memory impairments, which occur regularly across species as a result of aging, disease and psychological insults (for example, stress), constitute a useful area for investigation into the neurobiological basis of learning and memory. Memory researchers have identified the hippocampus as a crucial brain structure involved in key aspects of memory formation. The most widely accepted putative mechanisms of memory storage in this structure are LTP and LTD. The hippocampus is enriched with receptors for corticosterone (a glucocorticoid hormone released in response to stress) and it plays a role in glucocorticoid negative feedback and, therefore, some hippocampal functioning might be particularly susceptible to stress. In support of this view, stress-induced modifications in learning, synaptic plasticity and endangerment of neurons have been seen in the hippocampus. Stress and glucocorticoids appear to exert a metaplastic effect through the modulation of Ca2+ levels. We propose a synaptic model that provides a conceptual scaffold to structure our understanding of the manifold actions of stress on the hippocampus. Accordingly, we suggest that stress-induced metaplasticity could disrupt Ca2+ homeostasis and thus endanger hippocampal neurons.     

Presynaptic nigrostriatal function in genetically tested asymptomatic relatives from the pallido-ponto-nigral degeneration family

Pallido-ponto-nigral degeneration (PPND) is a dominantly inherited disorder with parkinsonism. We performed PET with [18F]fluorodopa (FD) and, later, gene testing in 12 asymptomatic relatives at risk from a family with PPND and compared the striatal FD uptake constant (Ki) in them with 4 symptomatic individuals and 10 normal control subjects. Four relatives with positive linkage had a significantly reduced Ki from the normal control subjects but to a lesser degree than the symptomatic patients. The mean Ki in the relatives with negative linkage (n = 8) did not differ from normal control subjects. In conclusion, we identified reduced dopaminergic function in asymptomatic relatives with positive genetic linkage from the PPND family. Most of the reduction in this disorder occurs in the fifth decade, when the disease manifests clinically.