Oscar A. Ramirez

Chronic stress-induced changes in locus coeruleus neuronal activity

Locus coeruleus (LC) activity was assessed in rats exposed to either acute or chronic stress. After one immobilization session, the number of spontaneously active LC neurons dramatically decreased. On the other hand, repeated restraint sessions enhanced noradrenergic (NA) transmission and the inhibitory effect of clonidine (CLON) was greater on these cells than in those of controls. These results bear on the adaptive changes in the NA system following acute or chronic stress.

Correlation between threshold to induce long-term potentiation in the hippocampus and performance in a shuttle box avoidance response in rats

The relationship between the learning ability of normal rats and the facility to induce long-term potentiation (LTP) in the same animals was investigated. Behavioral performance was measured in a shuttle box avoidance paradigm, using a buzzer as conditioned stimulus. Three days later animals were sacrificed; frequency threshold necessary to induce LTP was determined in transverse hippocampal slices taken from these animals and maintained in vitro. A linear regression analysis on the behavioral and electrophysiological data showed a negative correlation (Spearman rank correlation coefficient rs = -0.705; P less than 0.001) between percent of conditioned responses in the shuttle box and threshold frequency necessary to induce LTP in gyrus dentatus in response to tetanic stimulation of the perforant path. It is concluded that learning ability of normal rats in a shuttle box avoidance paradigm is correlated with hippocampal synaptic plasticity.

Role of cellular prion protein on LTP expression in aged mice

Cellular prion protein (PrP(c)) has been associated with some physiological functions in the last few years. In a previous paper, we have demonstrated an increased hippocampal synaptic transmission in adult mice lacking this protein. In the present study, we investigate the impact of aging on the generation and maintenance of hippocampal long-term Potentiation (LTP) in 9-month-old mice devoid of PrP(c) protein (Prnp(0/0)). We observed a lower threshold for inducing LTP in 9-month-old Prnp(0/0) mice compared to wild-type ones at the same age. The maintenance of dentate gyrus LTP was more persistent in hippocampal slices from Prnp(0/0) mice. Furthermore, the expression of mRNA for NR2A and NR2B subunits of the NMDA glutamatergic receptor in hippocampus of aged Prnp(0/0) animals showed an increase compared to the wild type. We propose that increased hippocampal glutamatergic transmission in Prnp(0/0) mice is related to the enhanced plasticity and persistence of the dentate LTP.

Increased susceptibility to LTP generation and changes in NMDA-NR1 and -NR2B subunits mRNA expression in rat hippocampus after MCH administration

The present study attempts to determine which mechanisms underlie the retrograde facilitation of memory induced by microinjection hippocampal melanin-concentrating hormone (MCH) on the inhibitory avoidance paradigm. Previous reports using this test on the hippocampus suggest that NMDA receptor-mediated mechanisms are involved in memory processing and are also necessary for the induction of long-term potentiation (LTP) of the hippocampal dentate gyrus. In addition, alterations in expression of synaptic NMDA subunits in the hippocampus have been associated with memory formation of an inhibitory avoidance task. We have studied the effects of the neuropeptide upon the electrophysiological parameters using hippocampal slices from rats injected with the peptide and tested in step-down tests as well as possible changes in the mRNA expression of NMDA receptor subunits. We postulate that the increased facility to induce LTP, and the overexpression of this N-methyl-D-aspartate mRNA receptor subunits induced by MCH, could be behind the retrograde facilitation observed after MCH hippocampal microinjection.

The learning capacity of high or low performance rats is related to the hippocampus NMDA receptors

The hippocampal synaptic plasticity of rats with an inborn high (HP) or low (LP) learning capacity to perform in a shuttle box is closely related to their percentage of conditioned responses (Crs). HP rats show less sensitivity to the blocking effect of 2-aminophosphonopentanoic acid (AP5) on the generation of long-term potentiation (LTP) than do LP rats. Results described in the present report are indicative of an increased density of N-methyl-D-aspartate (NMDA) receptors in HP rats compared to control and LP rats. We postulate that the differential pharmacological sensitivity of LTP in these rats is a reflection of this biochemical difference. Also, from these results we suggest that the learning capacity may be related to the density of glutamate NMDA receptors of HP, LP and control rats.

Gangliosides improve synaptic transmission in dentate gyrus of hippocampal rat slices

The effect of perfusion with gangliosides (1 x 10(-6) M) on the response evoked in the granule cell layer of dentate gyrus by stimulation of perforant path in hippocampal rat slices was studied. Gangliosides induced both a decrease in the frequency threshold of stimulation necessary to generate long-term potentiation (LTP) and greater potentiation than under control conditions. It is proposed that gangliosides improve the mechanisms responsible for synaptic plasticity which generate LTP.

Melanin concentrating hormone increase hippocampal synaptic transmission in the rat

A retrograde facilitation has been demonstrated in the one trial step-down inhibitory avoidance of melanin-concentrating hormone (MCH), when it was infused into rat hippocampal formation. Considering the high density of specific binding sites for the MCH peptide on the hippocampus and the participation of this structure on learning and memory processes we have studied the effects of MCH on the hippocampal synaptic transmission. For this purpose, slices of rat hippocampus were perfused with different concentration of MCH. The main result of the present study was a long-lasting potentiation on the hippocampal evoked response on dentate gyrus induced by MCH (4-11 microM) at 30, 60 and 120 min with a maximum effect at 120 min. Previous perfusion of DL - 2- amino - 5 phosphonovaleric acid (APV, 20 microM) was unable to impair the increased hippocampal evoked response induced by MCH 4 microM. On the other hand, the channel blocker Dizocilpine (MK-801, 10 microM) completely impaired the increased hippocampal synaptic plasticity induced by MCH perfusion. We postulate the increased hippocampal synaptic efficacy induced by MCH as one of the mechanisms underlying the retrograde facilitation on the inhibitory avoidance paradigm, observed after MCH hippocampal microinjection. We cannot rule out other MCH neurochemical mechanism and other areas of the brain involved in the MCH effects.

Time course effects of uncontrollable stress in locus coeruleus neuronal activity

The animals exposed to inescapable shock (IS) showed a behavioral depression which was assessed by the increased number of escape failures on an avoidance escape test, either 24 or 48 hours after. The number of noradrenergic (NA) spontaneously active cells of locus coeruleus (LC) appear to be increased 24 and 48 h later (IS) compared to control animals. On the other hand the firing rate at 24 and 48 hours was continuously decreased. The dose-response curve to inhibitory effect of clonidine (CLON) on firing rate of locus coeruleus (LC) neurons showed a clear shift to the right. These results are discussed in terms of the subsensitivity of alpha-2 adrenoceptor and a calcium-activated potassium current (IK(Ca)) controlling the firing rate of LC neurons and the increased release of noradrenaline induced by IS 24 or 48 h before.

Effects on the acquisition of conditioned avoidance responses and seizure threshold in the offspring of amphetamine treated gravid rats

Female rats with 30 to 70% of conditioned responses in an avoidance conditioning session in a Warner cage, were treated daily during pregnancy with 0.5 mg/kg of d,l-amphetamine administered subcutaneously. They had been mated with males selected with the same criterion who received no treatment.The control group differed from the treated one in that females received the same volume of saline solution instead of the drug.Teratogenic effects of the drug were not observed and there were no differences in either the age of eyes or vaginal aperture or in growth rate determined by the weekly weight between offspring of treated and control mothers.The pups of amphetamine treated mothers had better acquisition and retention of conditioned avoidance responses than those of control mothers when they were 90 days old but no difference was observed at the age of 45 days.On the other hand, offspring of the treated group had a lower hippocampal seizure threshold than the control group.The relation between the mechanisms of learning and seizure are discussed in connection with potassium release by stimulation in the hippocampus.

Differential threshold for long-term potentiation in the hippocampus of rats with inborn high or low learning capacity

Threshold of stimulation frequency in the perforant path to induce long-term potentiation (LTP) in dentate gyrus was determined in hippocampal slices obtained from two different lines of rats inbred for 30 generations according to their performance in an avoidance escape test in a shuttle box. High-performance (HP) rats were defined as those giving at least 70% conditioned responses (CRs) and low-performance (LP) rats as those giving less than 15% CRs. LTP was defined as a 30% or more increase in the amplitude of the evoked population spike (PS), lasting at least 20 min. Stimulation frequency threshold was determined by stimulating with a train of pulses of 0.5 ms duration during 1 s. The same slice was stimulated with trains of increasing frequency from 5 to 400 Hz, each train separated by an interval of at least 20 min. HP rats showed a lower threshold (13 +/- 4 Hz) than LP rats (92 +/- 42 Hz) for the induction of LTP; there were no differences in the magnitude of LTP. The greater learning ability of HP rats may be related to the plasticity of hippocampal synaptic transmission.