W.H. Gispen

Place Learning and Hippocampal Synaptic Plasticity in Streptozotocin-Induced Diabetic Rats

Moderate impairment of learning and memory has been recognized as a complication of diabetes. The present study examined behavioral and electrophysiological measures of cerebral function in streptozotocin (STZ)-induced diabetic rats. Behavioral testing consisted of a spatial learning task in a water maze. Electrophysiological testing consisted of in vitro assessment of hippocampal long-term potentiation (LTP), an activity-dependent form of synaptic plasticity, which is believed to be related to the cellular mechanisms of learning and memory. Two experiments were performed: the first with severely hyperglycemic rats and the second with moderately hyperglycemic rats. Rats were tested in the water maze 11 weeks after induction of diabetes. Next, LTP was measured in vitro in trained animals. Both spatial learning and LTP expression in the CA1 field of the hippocampus were impaired in severely hyperglycemic rats as compared with nondiabetic controls. In contrast, spatial learning and hippocampal LTP were unaffected in moderately hyperglycemic rats. The association of alterations in hippocampal LTP with specific learning impairments has previously been reported in conditions other than diabetes. Our findings suggest that changes in LTP-like forms of synaptic plasticity in the hippocampus, and possibly in other cerebral structures, are involved in learning deficits in STZ-induced diabetes. The beneficial effect of moderate glycemic control on both place learning and hippocampal LTP supports the significance of the relation between these two parameters and indicates that the development of the observed deficits may be related to the level of glycemic control.

Cerebral function in diabetes mellitus

SummaryDiabetes mellitus is a common metabolic disorder associated with chronic complications such as nephropathy, angiopathy, retinopathy and peripheral neuropathy. Diabetes is not often considered to have deleterious effects on the brain. However, long-term diabetes results in a variety of subtle cerebral disorders, which occur more frequently than is commonly believed. Diabetic cerebral disorders have been demonstrated at a neurochemical, electrophysiological, structural and cognitive level; however, the pathogenesis is still not clear. Probably alterations in cerebral blood supply and metabolic derangements play a role, as they do in the pathogenesis of diabetic neuropathy. Furthermore, the brain is also affected by recurrent episodes of hypoglycaemia and poor metabolic control. We describe herein the cerebral manifestations of diabetes and discuss the putative pathogenetic mechanisms.

Prevention of Cisplatin Neurotoxicity with an ACTH(4–9) Analogue in Patients with Ovarian Cancer

Abstract In a randomized, double-blind, placebo-controlled study, we assessed the efficacy of an ACTH(4–9) analogue, Org 2766, in the prevention of cisplatin neuropathy in 55 women with ovarian cancer. The analogue was given subcutaneously in a dose of 0.25 mg (low dose) or 1 mg (high dose) per square meter of body-surface area before and after treatment with cisplatin and cyclophosphamide (75 and 750 mg per square meter every three weeks). The threshold of vibration perception was used as the principal measure of neurotoxicity. After four cycles of chemotherapy, the mean (±SEM) threshold value for vibration perception in the placebo group increased from 0.67±0.12 to 1.61±0.43 μm of skin displacement (P<0.0001). In the high-dose treatment group, there was no increase in the threshold value after four cycles (from 0.54±0.12 to 0.50±0.06 μm). After six cycles of chemotherapy, the threshold value was 5.87±1.97 μm in the placebo group (more than an eightfold increase from base line), as compared with 0.88±0.1...

Presynaptic localization of B-50 phosphoprotein: the (ACTH)-sensitive protein kinase substrate involved in rat brain polyphosphoinositide metabolism

This study describes the ultrastructural localization in rat hippocampal tissue in situ and in isolated synaptosomes of the brain-specific phosphoprotein B-50, using affinity purified anti-B-50 immunoglobulins (IgGs). Evidence is presented for the presynaptic localization of B-50 in rat brain. Given this specific localization a model is presented outlining the presumed function of the B-50 protein in the membrane and describing possible neuromodulation by adrenocorticotropin hormone (ACTH)-like peptides.

Comparison of the immunocytochemical distribution of the phosphoprotein B 50 in the cerebellum and hippocampus of immature and adult rat brain

In this study we compare the distribution of the phosphoprotein B-50 in two regions of immature and adult rat brain using affinity-purified antibodies to B-50. In the cerebellum of the 8-day-old rat we observed distinct patterns of distribution of B-50 immunoreactivity (BIR) in the premigratory zone and the developing molecular layer, likely associated with outgrowing parallel and climbing fibers contacting Purkinje cells in the internal granular layer and in axons coursing through the cerebellar medulla. In contrast, in adult cerebellum, a sparcer distribution of BIR as punctuate deposits is observed in the molecular layer, outlining dendritic trees and the perikarya of neurons. At relatively lower density BIR is found dispersed between the cells of the granular layer and along fibers in the white matter. In the immature hippocampal formation, fibers penetrating between unstained cells of the stratum pyramidale and the subiculum, and neuropil areas are immunostained. In the adult rat a graded immunostaining pattern corresponding to the laminar structure of the hippocampal formation is found with high density of BIR in the strata oriens, radiatum, parts of stratum lacunosum molecular and in the stratum molecular adjoining the field of the proximal apical dendrites of the granule cells. BIR appears to be absent from the proximal part of the mossy fiber pathway. In neuropil areas of adult hippocampus and cerebellum BIR is fairly restricted to dot-like deposits indicating a synaptic localization. This is in correspondence with our previous ultrastructural findings. The present observations in developing brain of B-50-like components in fibers, as well, suggest that B-50 (and/or B-50-like precursors) are involved in neurite outgrowth.

Phosphorylation of B-50 (GAP43) is correlated with neurotransmitter release in rat hippocampal slices

Abstract: Recent studies have demonstrated that phorbol diesters enhance the release of various neurotransmitters. It is generally accepted that activation of protein kinase C (PKC) is the mechanism by which phorbol diesters act on neurotransmitter release. The action of PKC in neurotransmitter release is very likely mediated by phosphorylation of substrate proteins localized in the presynaptic nerve terminal. An important presynaptic substrate of PKC is B‐50. To investigate whether B‐50 mediates the actions of PKC in neurotransmitter release, we have studied B‐50 phosphorylation in intact rat hippocampal slices under conditions that stimulate or inhibit PKC and neurotransmitter release. The slices were labelled with [32P]orthophosphate. After treatment, the slices were homogenized, B‐50 was immunoprecipitated from the slice homogenate, and the incorporation of 32P into B‐50 was determined. Chemical depolarization (30 μM K+) and the presence of phorbol diesters, conditions that stimulate neurotransmitter release, separately and in combination, also enhance B‐50 phosphorylation. Polymyxin B, an inhibitor of PKC and neurotransmitter release, decreases concentration dependently the depolarization‐induced stimulation of B‐50 phosphorylation. The effects of depolarization are not detectable at low extracellular Ca2+ concentrations. It is concluded that in rat hippocampal slices B‐50 may mediate the action of PKC in neurotransmitter release.

Collagen Containing Neurotrophin-3 (NT-3) Attracts Regrowing Injured Corticospinal Axons in the Adult Rat Spinal Cord and Promotes Partial Functional Recovery ☆

During development, neurotrophic factors play an important role in the guidance and outgrowth of axons. Our working hypothesis is that neurotrophic factors involved in the development of axons of a particular CNS tract are among the most promising candidates for stimulating and directing the regrowth of fibers of this tract in the lesioned adult animal. The neurotrophin NT-3 is known to be involved in the target selection of outgrowing corticospinal tract (CST) fibers. We studied the capacity of locally applied NT-3 to stimulate and direct the regrowth of axons of the CST in the lesioned adult rat spinal cord. We also studied the effect of NT-3 application on the functional recovery of rats after spinal cord injury, using the gridwalk test. NT-3 was applied at the site of the lesion dissolved into rat tail collagen type I. Four weeks after spinal cord injury and collagen implantation, significantly more CST fibers had regrown into the collagen matrix containing NT-3 (22 +/- 6%, mean +/- SEM) than into the control collagen matrix without NT-3 (7 +/- 2%). No CST fibers grew into areas caudal to the collagen implant. Despite the absence of regrowth of corticospinal axons into host tissue caudal to the lesion area, functional recovery was observed in rats with NT-3 containing collagen implants.

Learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: interaction of diabetes and ageing

AbstractAims/hypothesis. Diabetes mellitus leads to functional and structural changes in the brain which appear to be most pronounced in the elderly. Because the pathogenesis of brain ageing and that of diabetic complications show close analogies, it is hypothesized that the effects of diabetes and ageing on the brain interact. Our study examined the effects of diabetes and ageing on learning and hippocampal synaptic plasticity in rats.¶Methods. Young adult (5 months) and aged (2 years) rats were examined after 8 weeks of streptozotocin-diabetes. Learning was tested in a Morris water maze. Synaptic plasticity was tested ex vivo, in hippocampal slices, in response to trains of stimuli of different frequency (0.05 to 100 Hz).¶Results. Statiscally significant learning impairments were observed in young adult diabetic rats compared with controls. These impairments were even greater in aged diabetic animals. In hippocampal slices from young adult diabetic animals long-term potentiation induced by 100 Hz stimulation was impaired compared with controls (138 vs 218 % of baseline). In contrast, long-term depression induced by 1 Hz stimulation was enhanced in slices from diabetic rats compared with controls (79 vs 92 %). In non-diabetic aged rats synaptic responses were 149 and 93 % of baseline in response to 100 and 1 Hz stimulation, compared with 106 and 75 % in aged diabetic rats.¶Conclusion/interpretation. Both diabetes and ageing affect learning and hippocampal synaptic plasticity. The cumulative deficits in learning and synaptic plasticity in aged diabetic rats indicate that the effects of diabetes and ageing on the brain could interact. [Diabetologia (2000) 43: 500–506]

Vasopressin and Memory Consolidation

Publisher Summary The hypothalamic-neurohypophyseal system possibly makes use of (a) the general circulation for peripheral effects of posterior pituitary hormones; (b) the portal vessel system for the regulation of anterior pituitary function; and (c) the cerebrospinal fluid for CNS activities. Evidence is presented in the chapter that vasopressin and its analogues facilitate the consolidation of learned behavior patterns. Under certain conditions, these peptides facilitate the acquisition of active avoidance behavior and increase the resistance to the extinction of active and passive avoidance behavior and of sexually motivated approach behavior as well. Intraventricular administration of minute amounts of vasopressin analogues facilitates memory consolidation. This supports the idea that the behavioral effect of these polypeptides is centrally mediated. Vasopressin antibodies, which are assumed to neutralize in situ vasopressin released into the cerebrospinal fluid (CSF), prevent memory consolidation. Studies on paradoxical sleep in diabetes insipidus rats reveal disturbances in hippocampal theta frequencies and strengthen the hypothesis that memory consolidation is under the influence of vasopressin analogues. The development of resistance to the analgesic action of narcotic analgesics is facilitated by the administration of vasopressin analogues and markedly retarded in diabetes insipidus rats. These and other results suggest that the memory consolidating effects of vasopressin analogues are of a more general nature.

Behavioral effects of peptides

The pituitary—adrenal system plays an essential role in homeostatic functions. Numerous aspects of stress-induced pituitary—adrenal activation in relation to peripheral mechanisms of adaptation have been studied since Selye’s first observations on the general adaptation syndrome some 40 years ago (Selye, 1950). Little attention, however, has been paid to the brain as a target for these hormones. Clinical observations frequently commented on psychological changes in addition to electrophysiological alterations in hyper- as well as hypocorticism (Cleghorn, 1957; Von Zerssen, 1976). Many a laboratory experiment during the last decade, however, disclosed the implication of a number of pituitary and hypothalamic hormonal peptides on various brain functions. The importance of these entities was revealed by observations on behavioral disturbances following extirpation of the pituitary gland in rats (de Wied, 1969); in animals with hereditary diabetes insipidus, which lack the ability to synthesize vasopressin (de Wied et al., 1975a); or in rats in which the action of vasopressin in the brain is neutralized by intraventricular administration of specific vasopressin antiserum (van Wimersma Greidanus et al., 1975a).