Effect of varying the intensity and train frequency of forelimb and cerebellar mossy fiber conditioned stimuli on the latency of conditioned eye-blink responses in decerebrate ferrets.
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To study the role of the mossy fiber afferents to the cerebellum in classical eye-blink conditioning, in particular the timing of the conditioned responses, we compared the effects of varying a peripheral conditioned stimulus with the effects of corresponding variations of direct stimulation of the mossy fibers. In one set of experiments, decerebrate ferrets were trained in a Pavlovian eye-blink conditioning paradigm with electrical forelimb train stimulation as conditioned stimulus and electrical periorbital stimulation as the unconditioned stimulus. When stable conditioning had been achieved, the effect of increasing the intensity or frequency of the forelimb stimulation was tested. By increasing the intensity from 1 to 2 mA, or the train frequency from 50 to 100 Hz, an immediate decrease was induced in both the onset latency and the latency to peak of the conditioned response. If the conditioned stimulus intensity/frequency was maintained at the higher level, the response latencies gradually returned to preshift values. In a second set of experiments, the forelimb stimulation was replaced by direct train stimulation of the middle cerebellar peduncle as conditioned stimulus. Varying the frequency of the stimulus train between 50 and 100 Hz had effects that were almost identical to those obtained when using a forelimb conditioned stimulus. The functional meaning of the latency effect is discussed. It is also suggested that the results support the view that the conditioned stimulus is transmitted through the mossy fibers and that the mechanism for timing the conditioned response is situated in the cerebellum. (+info)
Local dendritic Ca2+ signaling induces cerebellar long-term depression.
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The coordinated activity of large numbers of adjacent parallel fiber synapses elevate calcium concentration locally in small regions of Purkinje cell dendrites. Such activity has also been reported to produce long-term depression of parallel fiber synaptic transmission. We have examined the relationship between these two events by combining patch clamp measurements of parallel fiber synaptic transmission with confocal microscopic imaging of the local calcium signals. We find that patterns of parallel fiber activity capable of evoking long-term depression invariably cause increases in Purkinje cell calcium concentration that are very spatially restricted. These results suggest that one function of the local dendritic calcium signals is to induce long-term depression of parallel fiber synapses. (+info)
Absence of cerebellar long-term depression in mice lacking neuronal nitric oxide synthase.
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Extensive pharmacological evidence suggests that nitric oxide (NO) is a crucial transmitter for cerebellar long-term depression (LTD), a long-lasting decrease in efficacy of the synapses from parallel fibers onto Purkinje neurons, triggered by coincident presynaptic activity and postsynaptic depolarization. We now show that LTD cannot be induced in Purkinje neurons under whole-cell patch clamp in cerebellar slices from young adult mice genetically lacking neuronal nitric oxide synthase (nNOS). This genetic evidence confirms the essentiality of NO and nNOS for LTD in young adult rodents. Surprisingly, LTD in cells from nNOS knockout mice cannot be rescued by photolytic uncaging of NO and cGMP inside Purkinje neurons, although such stimuli circumvent acute pharmacological inhibition of nNOS and soluble guanylate cyclase in normal rodents. Also slices from knockout mice show no deficit in cGMP elevation in response to exogenous NO. Therefore, prolonged absence of nNOS allows atrophy of the signaling pathway downstream of cGMP. (+info)
Vision affects mushroom bodies and central complex in Drosophila melanogaster.
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The brain of Drosophila is structurally altered by sensory stimuli that the flies receive during their adult life. Size and fiber number of the mushroom bodies, central complex, and optic lobes are influenced by social, spatial, or olfactory cues. Recently, the optic lobes have been shown to depend on the light regime that flies experience. Structural plasticity in the brain is thought to be a correlate of functional adaptations and long-term memory. We therefore extend our investigation of volume changes to the calyces of the mushroom bodies and the central complex. We show that rearing flies in constant light for 4 days increases the volume of both structures by up to 15% compared to rearing them in total darkness. Much of this difference develops during the first day. The effect of light is not hormonally mediated, as monocularly deprived flies develop a smaller ipsilateral calyx. Mutant analysis suggests that light generates its effects through known visual pathways. In contrast to the optic lobes, in the calyx and central complex structural changes can be linked to cAMP signaling, as in the mutants dunce1 and amnesiac1 no volume differences are observed. Surprisingly, the mutant rutabaga1 shows a prominent light-dependent volume increase in the calyx and central complex, dissociating structural from behavioral plasticity. In complete darkness wild-type flies grow larger calyces under crowded conditions in their normal culture vials than if kept in small groups on fresh food. This stimulating effect of crowding is not observed in any of the cAMP mutants, including rutabaga1. (+info)
Ionic basis for plateau potentials in deep dorsal horn neurons of the rat spinal cord.
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Approximately 28% of dorsal horn neurons (DHNs) in lamina V of the rat spinal cord generate voltage-dependent plateau potentials underlying accelerating discharges and prolonged afterdischarges in response to steady current pulses or stimulation of nociceptive primary afferent fibers. Using intracellular recordings in a transverse slice preparation of the cervical spinal cord, we have analyzed the ionic mechanisms involved in the generation and maintenance of plateau potentials in lamina V DHNs. Both the accelerating discharges and afterdischarges were reversibly blocked by Mn(2+) and enhanced when Ca(2+) was substituted with Ba(2+). The underlying tetrodotoxin-resistant regenerative depolarization was sensitive to dihydropyridines, being blocked by nifedipine and enhanced by Bay K 8644. Substitution of extracellular Na(+) with N-methyl-D-glucamine or choline strongly decreased the duration of the plateau potential. Loading the neurons with the calcium chelator BAPTA did not change the initial response but clearly decreased the maximum firing frequency and the duration of the afterdischarge. A similar effect was obtained with flufenamate, a specific blocker of the calcium-activated nonspecific cation current (I(CAN)). We conclude that the plateau potential of deep DHNs is supported by both Ca(2+) influx through intermediate-threshold voltage-gated calcium channels of the L-type and by subsequent activation of a CAN current. Ca(2+) influx during the plateau is potentially of importance for pain integration and the associated sensitization in spinal cord. (+info)
Autonomic dysreflexia is a condition that develops after spinal cord injury in which potentially life-threatening episodic hypertension is triggered by stimulation of sensory nerves in the body below the site of injury. Central sprouting of small-diameter primary afferent fibers in the dorsal horn of the spinal cord occurs concurrently with the development of this condition. We propose a model for the development of autonomic dysreflexia in which increased nerve growth factor (NGF) in the injured cord stimulates small-diameter primary afferent fiber sprouting, thereby magnifying spinal sympathetic reflexes and promoting dysreflexia. We identified this population of afferent neurons using immunocytochemistry for calcitonin gene-related peptide. Blocking intraspinal NGF with an intrathecally-delivered neutralizing antibody to NGF prevented small-diameter afferent sprouting in rats 2 weeks after a high thoracic spinal cord transection. In the same rats, this anti-NGF antibody treatment significantly decreased (by 43%) the hypertension induced by colon stimulation. The extent of small-diameter afferent sprouting after cord transection correlated significantly with the magnitude of increases in arterial pressure during the autonomic dysreflexia. Neutralizing NGF in the spinal cord is a promising strategy to minimize the life-threatening autonomic dysreflexia that develops after spinal cord injury. (+info)
Redundant basal forebrain modulation in taste aversion memory formation.
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Mnemonic deficits resulting from excitotoxic lesion of the basal forebrain have been classically attributed to the resulting depletion of cortical acetylcholine activity. It has been demonstrated that in spite of the strong cholinergic depletion after injections into the basal forebrain of the immunotoxin 192IgG-saporin, no detectable deficit can be found in the acquisition of several learning tasks, including conditioned taste aversion. Conversely, NMDA-induced lesions of the basal forebrain strongly impair taste aversion learning. In this study we show that 192IgG-saporin produces an efficient and selective cholinergic deafferentation of the rat neocortex but not the amygdala. Furthermore, a stronger relationship between severity of memory impairment after NMDA lesions and basoamygdaloid cholinergic deafferentation was found. Therefore, in a second experiment, we show that combining NMDA-induced lesions into the basolateral amygdala with 192IgG-saporin injections into the basal forebrain results in a strong disruption of taste aversion learning, whereas none of these treatments were by themselves capable of producing any detectable impairment in this learning task. The double lesion effect was only paralleled by simple NMDA lesions into the basal forebrain, suggesting that the learning deficits associated to excitotoxic lesions of the basal forebrain are the result of the simultaneous destruction of the corticopetal and basoamygdaloid interaction. A model is proposed, according to which the modulation of learning processes exerted by the basal forebrain can be redundantly performed by both the basocortical and basoamygdaloid pathway. (+info)
Substance P relaxes rat bronchial smooth muscle via epithelial prostanoid synthesis.
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BACKGROUND: Substance P is present in bronchial nerve fibres. The physiological actions of substance P are mediated via tachykinin NK(1) receptors. Immunochemical studies have demonstrated tachykinin NK(1) receptors in the rat airway epithelium. OBJECTIVE: To elucidate how epithelial tachykinin NK(1) receptors affect smooth muscle response to substance P. METHODS: Contractile response of isolated rat bronchial trunk with or without epithelium was recorded. RESULTS: In intact segments precontracted by 5-hydroxytryptamine, relaxation was induced by substance P and the nitric oxide donor, sodium nitroprusside. Removal of the epithelium abolished relaxation induced by substance P but did not affect relaxation induced by sodium nitroprusside. The cyclo-oxygenase inhibitor, indomethacin, but not the nitric oxide synthase inhibitor, L-N(G)-monomethylarginine, reduced the relaxation in response to substance P. CONCLUSIONS: Epithelial tachykinin NK(1) receptors mediate substance-P-induced relaxation of rat bronchial smooth muscle via release of prostanoids but not nitric oxide. (+info)