I.J.A. Urban

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.

Water maze learning and hippocampal synaptic plasticity in streptozotocin diabetic rats: effects of insulin treatment

Streptozotocin-diabetic rats express deficits in water maze learning and hippocampal synaptic plasticity. The present study examined whether these deficits could be prevented and/or reversed with insulin treatment. In addition, the water maze learning deficit in diabetic rats was further characterized. Insulin treatment was commenced at the onset of diabetes in a prevention experiment, and 10 weeks after diabetes induction in a reversal experiment. After 10 weeks of treatment, insulin-treated diabetic rats, untreated diabetic rats and non-diabetic controls were tested in a spatial version of the Morris water maze. Next, hippocampal long-term potentiation (LTP) was measured in vitro. To further characterize the effects of diabetes on water maze learning, a separate group of rats was pre-trained in a non-spatial version of the maze, prior to exposure to the spatial version. Both water maze learning and hippocampal LTP were impaired in diabetic rats. Insulin treatment commenced at the onset of diabetes prevented these impairments. In the reversal experiment, insulin treatment failed to reverse established deficits in maze learning and restored LTP only partially. Non-spatial pre-training abolished the performance deficit of diabetic rats in the spatial version of the maze. It is concluded that insulin treatment may prevent but not reverse deficits in water maze learning and LTP in streptozotocin-diabetic rats. The pre-training experiment suggests that the performance deficit of diabetic rats in the spatial version of the water maze is related to difficulties in learning the procedures of the maze rather than to impairments of spatial learning.

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.

Hippocampal synaptic plasticity in streptozotocin-diabetic rats: impairment of long-term potentiation and facilitation of long-term depression

Streptozotocin-diabetic rats, an animal model for diabetes mellitus, show learning deficits and impaired long-term potentiation in the CA1-field of the hippocampus. The present study aimed to further characterize the effects of streptozotocin-diabetes on N-methyl-D-aspartate receptor-dependent long-term potentiation in the CA1-field, to extend these findings to N-methyl-D-aspartate receptor-dependent and independent long-term potentiation in other regions of the hippocampus and to examine effects on long-term depression. First, the effect of diabetes duration on long-term potentiation in the CA1-field was determined. A progressive deficit was observed after a diabetes duration of six to eight weeks, which reached a maximum after 12 weeks of diabetes and remained stable thereafter. Next, long-term potentiation was examined in the dentate gyrus and in the CA3-field after 12 weeks of diabetes. Both were found to be impaired compared to controls. Finally, long-term depression was examined in the CA1-field of the hippocampus after 12 weeks of diabetes and found to be enhanced in slices from diabetic rats compared to controls. Changes in synaptic plasticity were observed in hippocampal slices from streptozotocin-diabetic rats. Expression of N-methyl-D-aspartate receptor-dependent long-term potentiation was impaired in the CA1-field and dentate gyrus and expression of N-methyl-D-aspartate receptor-independent long-term potentiation was impaired in the CA3-field. In contrast, expression of long-term depression was facilitated in CA1. It is suggested that this combination of changes in plasticity may reflect alterations in intracellular signalling pathways.

Neuropeptides: Effects on paradoxical sleep and theta rhythm in rats

In a search for the mechanism by which neuropeptides influence the maintenance of avoidance behavior, a study was done of the effects of ACTH 4–10, arginine8-vasopressin (AVP), desglycinamide9-arginine8-vasopressin (DG-AVP), and of AVP antiserum on paradoxical sleep (PS) production and on theta activity generated during PS. Brattleboro rats which were homozygous (HO-DI) and heterozygous (HE-DI) for diabetes insipidus and homozygous normal (HO-NO) animals were used. The absence of AVP in HO-DI animals did not interfere with the production of PS during 8 hr recording sessions. However, it was found that the hippocampal theta activity of these animals exhibited significantly lower mean and peak frequencies than that of HE-DI or HO-NO rats. The deviation in the frequency content of the theta activity of HO-DI animals could be temporarily normalized by intraventricular injection of DG-AVP or ACTH 4–10. Inactivation of AVP in the brain of HO-NO rats by intraventricularly administered AVP antiserum induced hippocampal rhythmicity of the same frequency composition as that of HO-DI animals. Furthermore, intracerebroventricular administration of DG-AVP or ACTH 4–10 which both facilitate resistance to extinction of avoidance behavior [8,14], increased the proportion of high theta frequencies, whereas treatment with [D-phe7] ACTH 4–10, which facilitates extinction of active avoidance behavior [8], decreased the proportion of high frequency components in hippocampal activity of HE-DI animals. In addition, [D-phe7] ACTH 4–10 decreased the amount of high and increased the amount of low frequencies in the theta rhythm of HO-NO rats. None of the peptides tested appreciably affected the amount of PS. The experiments suggest that the increased resistance to extinction of avoidance behavior seen after the administration of neuropeptides related to vasopressin and ACTH could result from a longlasting increase in excitability induced by these substances in midbrain limbic circuits.

Long-term potentiation and synaptic protein phosphorylation

Long-term potentiation (LTP) is a well known experimental model for studying the activity-dependent enhancement of synaptic plasticity, and because of its long duration and its associative properties, it has been proposed as a system to investigate the molecular mechanisms of memory formation. At present, there are several lines of evidence that indicate that pre- and postsynaptic kinases and their specific substrates are involved in molecular mechanisms underlying LTP. Many studies focus on the involvement of protein kinase C (PKC). One way to investigate the role of PKC in long-term potentiation is to determine the degree of phosphorylation of its substrates after in situ phosphorylation in hippocampal slices. Two possible targets are the presynaptic membrane-associated protein B-50 (a.k.a. GAP 43, neuromodulin and F1), which has been implicated in different forms of synaptical plasticity in the brain such as neurite outgrowth, hippocampal LTP and neurotransmitter release, and the postsynaptic protein neurogranin (a.k.a. RC3, BICKS and p17) which function remains to be determined. This review will focus on the protein kinase C activity in pre- and postsynaptic compartment during the early phase of LTP and the possible involvement of its substrates B-50 and neurogranin.

Changes in excitability of the theta activity generating substrate by ACTH 4–10 in the rat

SummaryThe present experiments tested the sensitivity of theta activity to ACTH 4–10 a peptide known to facilitate the maintenance of conditioned behaviors. Hippocampal theta activity was induced by electrical stimulation of the reticular formation in freely moving rats. The administration of ACTH 4–10 produced a typical 0.5 c/s shift in dominant frequency and an increase in 7.5–9.0 c/s components of induced theta activity. The effects were maximal between 60–120 min after subcutaneous injection and lasted several hours. The fact, that a similar effect could be obtained by an increase in stimulus intensity suggests an elevated excitability in the theta generating system in the presence of the peptide. The possible significance of this finding for the maintenance of learned behavior is discussed.

Arginine8-Vasopressin Enhances the Responses of Lateral Septal Neurons in the Rat to Excitatory Amino Acids and Fimbria-Fornix Stimuli*

In the present study we investigated the effect of arginine-vasopressin (AVP) on responses induced in lateral septal neurons of the rat by iontophoretically administered excitatory and inhibitory amino acids and by synaptical stimuli delivered through fimbria-fornix (fi-fx) fibers. In the majority of the lateral septal neurons, iontophoretically applied AVP induced a marked increase in the excitatory responses to glutamate, aspartate, quisqualate and N-methyl-D-aspartate. The responses to excitatory amino acids frequently remained elevated several minutes after termination of the peptide administration. Inhibitory responses induced by GABA were not affected by AVP. The responsiveness of lateral septal single units to fi-fx stimuli was enhanced during iontophoretic administration of AVP. The enhanced responsiveness also appeared from experiments in which topically applied AVP induced a prolonged increase in the negative but not the positive wave of field potentials evoked in the lateral by fi-fx stimuli. The possible physiological significance of these findings is discussed.

The impaired long-term potentiation in the CA1 field of the hippocampus of cognitive deficient microencephalic rats is restored by D-serine

Rat embryos exposed on gestational day 15 to methyl-azoxymethanol acetate develop a microencephaly characterized primarily by a hypoplasia of the neocortex and CA fields of the hippocampus that in adulthood is associated with disturbances in learning. In brain slices prepared from microencephalic rats, we have examined the field excitatory postsynaptic potentials and population spike in the CA1 field of the hippocampus evoked by stimulation of the stratum radiatum. These parameters did not differ from those obtained in slices from control rats. High frequency stimulation of the stratum radiatum afferent fibres, which readily induced long-term potentiation of the field excitatory postsynaptic potentials and population spike in the CA1 field of the hippocampus of control rats, failed to induce long-term potentiation in that of microencephalic rats. High frequency stimulation of the perforant path readily elicited long-term potentiation in the dentate gyrus of both control and microencephalic rats. Picrotoxin had no apparent effect on field excitatory postsynaptic potentials and population spike in the CA1 field of the microencephalic rats, indicating that little GABAergic inhibition was present in slices from these rats. D-2-Amino-phosphonovalerate suppressed the field potentials in slices from microencephalic rats by more than 50%, suggesting that N-methyl-D-aspartate receptors contributed markedly to the synaptic responses evoked by single stimuli. D-Serine, but not picrotoxin, restored long-term potentiation in the CA1 field of the microencephalic rats. The D-serine effect was prevented by pretreating the slices with either 7-chloro-kynurenate or D-2-amino-phosphonovalerate. The failure to induce long-term potentiation, if also found in vivo, may be among the factors related to the learning deficits displayed by these rats.

Vasopressin maintains long-term potentiation in rat lateral septum slices

In brain slices of normal Wistar and Long-Evans rats, brief high frequency stimulation of the fimbria fibers induced long-term potentiation (LTP) in excitatory transmission between these fimbria fibers and neurons of the lateral septum (LS). Slices prepared from diabetes insipidus (DI) Brattleboro rats, that contained no vasopressin (VP), consistently failed to maintain LTP in this excitatory transmission. Exogenous VP, administered to slices from DI Brattleboro rats shortly prior to the experiment or released from a subcutaneous depot in DI Brattleboro rats for several days prior to decapitation, corrected this failure. The maintenance of LTP in the LS in slices from Wistar and Long-Evans rats was prevented by D(CH2)5-Tyr(Me)-arginine VP, an antagonist for the V1 type of VP receptors. These results indicate an important role of VP in the maintenance of LTP in excitatory transmission in the LS. It is conjectured that the effects of VP on LS neurons are related to the role of the peptide in the maintenance of LTP and that these processes play a role in memory formation.