A double dissociation within the hippocampus of dopamine D1/D5 receptor and beta-adrenergic receptor contributions to the persistence of long-term potentiation.

We compared the effects of the D1/D5 receptor antagonist SCH-23390 with the beta-adrenergic receptor antagonist propranolol on the persistence of long-term potentiation in the CA1 and dentate gyrus subregions of the hippocampus. In slices, SCH-23390 but not propranolol reduced the persistence of long-term potentiation in area CA1 without affecting its induction. The drugs exerted reverse effects in the dentate gyrus, although in this case the induction of long-term potentiation was also affected by propranolol. The lack of effect of SCH-23390 on the induction and maintenance of long-term potentiation in the dentate gyrus was confirmed in awake animals. The drug also had little or no effect on the expression of inducible transcription factors. In area CA1 of awake animals, SCH-23390 blocked persistence of long-term potentiation beyond 3 h, confirming the results in slices. To rule out a differential release of catecholamines induced by our stimulation protocols between brain areas, we compared the effects of the D1/D5 agonist SKF-38393 with the beta-adrenergic agonist isoproterenol on the persistence of a weakly induced, decremental long-term potentiation in CA1 slices. SKF-38393 but not isoproterenol promoted greater persistence of long-term potentiation over a 2-h period. In contrast, isoproterenol but not SKF-38392 facilitated the induction of long-term potentiation. These data demonstrate that there is a double dissociation of the catecholamine modulation of long-term potentiation between CA1 and the dentate gyrus, suggesting that long-term potentiation in these brain areas may be differentially consolidated according to the animal's behavioural state.

Abolition of long-term stability of new hippocampal place cell maps by NMDA receptor blockade.

Hippocampal pyramidal cells are called place cells because each cell tends to fire only when the animal is in a particular part of the environment-the cell's firing field. Acute pharmacological blockade of N-methyl-D-aspartate (NMDA) glutamate receptors was used to investigate how NMDA-based synaptic plasticity participates in the formation and maintenance of the firing fields. The results suggest that the formation and short-term stability of firing fields in a new environment involve plasticity that is independent of NMDA receptor activation. By contrast, the long-term stabilization of newly established firing fields required normal NMDA receptor function and, therefore, may be related to other NMDA-dependent processes such as long-term potentiation and spatial learning.

A dose of MK801 previously shown to impair spatial learning in the radial maze attenuates primed burst potentiation in the dentate gyrus of freely moving rats.

Spatial learning but not memory performance in the radial maze is disrupted by low doses of MK801 (0.0625 mg/kg ip), a noncompetitive N-methyl-D-aspartate receptor channel blocker (M. L. Shapiro & C. O'Connor, 1992). The effect of this low dose of MK801 on hippocampal physiology and synaptic plasticity was assessed in 16 behaving female Sprague-Dawley rats. The drug increased the frequency (0.5 Hz), marginally reduced the amplitude of hippocampal rhythmical slow wave activity (RSA), did not alter non-RSA slow wave activity, and reduced normal synaptic transmission from the entorhinal cortex to the dentate gyrus by approximately 8%. Independent of these effects on normal physiology. MK-801 also reduced primed burst potentiation, a form of synaptic plasticity produced by physiologically patterned stimulation, by approximately 20% in the same pathway. Thus, low doses of MK801 may impair spatial learning by reducing, directly or indirectly, the likelihood of synaptic plasticity in the hippocampus.

Reaching to ipsilateral or contralateral targets: within-hemisphere visuomotor processing cannot explain hemispatial differences in motor control.

Aiming movements made to visual targets on the same side of the body as the reaching hand typically show advantages as compared to aiming movements made to targets on the opposite side of the body midline in the contralateral visual field. These advantages for ipsilateral reaches include shorter reaction time, higher peak velocity, shorter duration and greater endpoint accuracy. It is commonly hypothesized that such advantages are related to the efficiency of intrahemispheric processing, since, for example, a left-sided target would be initially processed in the visual cortex of the right hemisphere and that same hemisphere controls the motor output to the left hand. We tested this hypothesis by examining the kinematics of aiming movements made by 26 right-handed subjects to visual targets briefly presented in either the left or the right visual field. In one block of trials, the subjects aimed their finger directly towards the target; in the other block, subjects were required to aim their movement to the mirror symmetrical position on the opposite side of the fixation light from the target. For the three kinematic measures in which hemispatial differences were obtained (peak velocity, duration and percentage of movement time spent in deceleration), the advantages were related to the side to which the motor response was directed and not to the side where the target was presented. In addition, these effects tended to be larger in the right hand than in the left, particularly for the percentage of the movement time spent in deceleration. The results are interpreted in terms of models of biomechanical constraints on contralateral movements, which are independent of the hemispace of target presentation.

Detailed behavioral analysis of water maze acquisition under systemic NMDA or muscarinic antagonism: nonspatial pretraining eliminates spatial learning deficits.

A detailed behavioral analysis of water-maze acquisition showed that the N-methyl-D-aspartate (NMDA) antagonist NPC17742 and the muscarinic antagonist scopolamine caused sensorimotor disturbances in behaviors required for maze performances and that these correlated with acquisition impairments in both hidden and visible platform versions of the maze in male rats. Behavioral disturbances included thigmotaxic swimming, swimming over and deflecting off the platform, abnormal swim behavior, and hyperactivity. Rats familiar with the behavioral strategies involved in the task performed normally under NPC17742 or scopolamine. The results indicated that drug-induced sensorimotor disturbances contributed to poor acquisition scores in naive rats. NMDA or muscarinic activity may contribute to but do not appear to be essential for spatial learning in the water maze.

Detailed behavioral analysis of water maze acquisition under APV or CNQX: contribution of sensorimotor disturbances to drug-induced acquisition deficits.

N-methyl-D-aspartate (NMDA) receptor antagonists disrupt acquisition of the water maze and cause sensorimotor disturbances. In a detailed behavioral analysis in male rats, it was found that the NMDA antagonist DL-2-aminophosphonovaleric acid (APV) caused sensorimotor disturbances in behaviors required for maze performance and that these correlated with acquisition impairments in both hidden and visible platform versions of the maze. Behavioral disturbances included thigmotaxic swimming, swimming over and deflecting off the platform, abnormal swim behavior, and hyperactivity. Rats familiar with the behavioral strategies involved in the task performed normally under APV. The results are consistent with the known role of NMDA receptors in sensorimotor mechanisms and suggest that drug-induced sensorimotor disturbances contributed to poor acquisition scores in naive rats. NMDA may contribute to but does not appear to be essential for spatial learning in the water maze.

Fyn tyrosine kinase is required for normal amygdala kindling.

To identify specific genes involved with epileptogenesis kindling was examined in mice carrying mutations engineered by gene targeting. Amygdala kindling was tested in mice with a null-mutation in the Fyn tyrosine kinase gene, a mutation that raises the threshold for the induction of long-term potentiation in the hippocampus. The fyn mutants had a normal threshold, duration and stability of epileptiform after-discharge, which is crucial for kindling. Despite the normal after-discharge, fyn mutants showed a striking retardation in the rate of kindling. Once the kindled state was established in fyn mutants it remained stable. This implicates a Fyn-dependent biochemical pathway in the induction but not the maintenance of normal amygdala kindling. fyn is the first gene identified to be required for normal epileptogenesis.

p-chlorophenylalanine-induced serotonin depletion: reduction in exploratory locomotion but no obvious sensory-motor deficits.

Para-chlorophenylalanine (PCPA) depletes central serotonin (5-hydroxytryptamine, 5-HT) by inhibiting tryptophan hydroxylase, an enzyme necessary for the synthesis of 5-HT. The effects of a wide range of PCPA doses (150-1000 mg/kg) on spontaneous exploratory locomotor activity in a novel environment, activity in running wheels and a number of sensory-motor capacities were examined. Administration of 1000 mg/kg PCPA reduced whole brain levels of 5-HT and its metabolite 5-hydroxyindoleacetic acid to 9.4 and 8.2% of control levels, respectively. Treatment with PCPA produced a dose-dependent decrease in exploratory locomotion in an unfamiliar automated open field relative to vehicle-treated animals. Further, all measures of general, horizontal and vertical activity were suppressed by PCPA treatment. In contrast to previous work, hyperactivity of rats chronically housed in cages with running wheel access was not observed. In their home cages, some PCPA-treated rats exhibited hyper-reactivity to cutaneous stimulation. No other sensory-motor deficits were apparent. Previous theories of 5-HT function state that its action may be to inhibit motor activity or promote sleep. The present results challenge this view and suggest that 5-HT, at least in certain environments, may stimulate locomotor activity without directly controlling various sensory-motor capacities in rats.

A multivariate assessment of spontaneous locomotor activity in the Mongolian gerbil (Meriones unguiculatus): influences of age and sex.

A multivariate assessment of the spontaneous locomotor activity of male and female Mongolian gerbils (Meriones unguiculatus) was obtained using a Digiscan automated animal activity monitoring system. Spontaneous motor activity data were collected over 1 h (5-min samples) for groups of male and female gerbils ranging from 26-341 days of age (26, 38, 62, 116, 151, 172, 196, 247, and 341). Variables examined included: total distance travelled, average distance per movement, average speed, number of horizontal movements, time in horizontal movement, time per horizontal movement, number of vertical movements, time in vertical movement, and time per vertical movement. Age had a significant effect on spontaneous activity; all measures of horizontal activity increased from preadulthood (26 and 38 days) and remained relatively constant thereafter for adults (62+ days). Vertical activity (rearing) measures were found to increase from the 62-day-old group to the 151- and 172-day-old groups and then decrease among the older groups (196+ days). Across the 12 samples, within sessions, all horizontal and vertical activity measures (except average speed) declined for both males and females. Habituation was more rapid for the preadults than for the adults on all horizontal measures except average distance per movement. No consistent sex differences in locomotor activity were found.

MK801-induced hyperactivity: duration of effects in rats.

MK801, a noncompetitive NMDA antagonist, induces hyperactivity, the duration of which is unknown. Thus, the hyperactivity induced by three different doses of MK801 was measured for 4 h using an automated open-field system. Adult male rats were habituated to the monitors for 1 h immediately prior to data collection. Rats were then administered one of three doses (0.05 mg/kg, n = 15; 0.1 mg/kg, n = 14; 0.5 mg/kg, n = 11) of MK801 or equivalent volumes of saline (n = 14). Upon injection, individual monitors were activated, and 48 consecutive 5-min samples were collected. Results indicated that MK801 induced hyperactivity in a dose-dependent fashion, with the two lower doses being significantly different from saline controls, but not from each other. The 0.5 mg/kg dose indicated that the peak behavioral activation occurred approximately 30 min after administration. This was followed by either a slow decline or a plateau phase, dependent upon the measure examined. By approximately 3 h after administration all measures had returned to the level of saline controls.

Brain temperature- and behavior-related changes in the dentate gyrus field potential during sleep, cold water immersion, radiant heating, and urethane anesthesia.

The field potential evoked in the dentate gyrus (DG) by stimulation of the perforant path (PP) is known to vary with ongoing behavior and with brain temperature. To further study these phenomena chronic stimulating and recording electrodes were implanted into the PP and DG of rats, and a thermistor was implanted into the contralateral homotopic DG. Field potentials and brain temperature records were made during (1) slow wave sleep (SWS), (2) radiant heating, (3) immersion in cool water, (4) a control session during which no manipulations were made, and (5) under urethane anesthesia. In another group of rats field potentials were recorded during (1) baseline immobile wakefulness, (2) SWS, (3) before SWS or after gentle awakening from SWS (eyes open and presence of intermittent slow waves in the EEG), (4) immobile wakefulness, and (5) 24 h later. Findings were that field EPSP slope decreased and population spike (PS) amplitude increased by up to 60% of baseline values during conditions in which brain temperature was reduced (SWS, immersion in cool water, urethane anesthesia). Conversely, EPSP slope increased and PS amplitude decreased by up to 100% of baseline values during conditions in which brain temperature increased (awakening from SWS, radiant heating, and warming after immersion in cool water or urethane anesthesia). Product moment correlations between brain temperature and field potential measures confirmed the statistical reliability of these findings and accounted for up to 77% of the variance. These findings confirm the robust effect on hippocampal field potentials of brain temperature changes due to exogenous heating and cooling, and extend this effect to anesthetic- and sleep-induced brain temperature changes. They also identify a state that behaviorally resembles quiet wakefulness but resembles SWS in terms of neocortical EEG, brain temperature, and hippocampal field potential measures. The findings indicate the need to control for brain temperature-mediated changes in hippocampal research that uses the dentate gyrus field potential as a dependent measure.

Reductions in body temperature and spontaneous activity in rats exposed to horizontal rotation: abolition following chemical labyrinthectomy.

The effect of horizontal rotation of male rats (70 rpm) on core temperature and spontaneous motor activity levels was examined. In Experiment 1, subjects were chemically labyrinthectomized (VNX) by intratympanic (IT) injections of sodium arsanilate and control rats (VNS) received IT injections of saline. Half of the rats in each group were subsequently rotated and the other half sham rotated. Measurement of body temperature prior to, immediately after, and 20 min following rotation revealed significant (all p < 0.01) reductions in temperature immediately after treatment, and 20 min later, in VNS rats. Sham-rotated VNS and all VNX rats failed to exhibit any significant changes in temperature following treatment. In Experiment 2, motor activity level was monitored in chemically labyrinthectomized (VNX) and control (VNS) rats prior to, and following, horizontal rotation. The VNS rats exhibited large (all p < 0.01) depressions in measures of horizontal and vertical spontaneous motor activity following rotation treatment, whereas VNX rats exhibited similar levels of activity in the pre- and postrotation period. These experiments show that, as in humans, exposing rats to horizontal rotation results in reduction of body temperature and motor activity, and that these physiological and behavioral changes require a functional vestibular system.

Sexually dimorphic spatial learning varies seasonally in two populations of deer mice.

Spatial learning in photoperiodically induced breeding (reproductive) and non-breeding (non-reproductive) adult male and female deer mice (Peromyscus maniculatus) was examined in a Morris water-maze task. Sexually mature, adult male and female deer mice that were derived from either a mainland population (P. m. artemisiae) or an island population (P. m. angustus) were required to learn the spatial position of a hidden, submerged platform in a water maze. Deer mice were tested either during the breeding season (summer; long day photoperiod) or during the non-breeding season (winter; short day photoperiod) with a total of six blocks of four trials conducted in a single day. Retention was tested with two probe trials which occurred one and three days after acquisition. During the breeding season male spatial task acquisition was superior to female spatial task acquisition for both populations. In contrast, during the non-breeding season there were no significant sex differences in spatial acquisition for either population. This change in sexually dimorphic spatial learning was due to female spatial-performance decreasing from non-breeding season to the breeding season and male spatial-performance increasing over the same period. Both populations displayed similar seasonal variations in sexually dimorphic water-maze task performance. There were, however, overall population differences in water-maze task performance that were related to the ecology of the mice, with the insular mice displaying shorter latencies to reach the hidden platform than did the mainland deer mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Polypropylene pellets as an inexpensive reusable substitute for milk in the Morris milk maze.

A new inexpensive opaquing agent for the Morris milk maze is described. Small light-weight polypropylene pellets that float on the surface of the water were used to eliminate visual cues about the location of the hidden platform without impeding swimming or the use of distal spatial cues. Results obtained using the pellets are identical to those obtained with milk powder as an opaquing agent. An automatic tracking system works as well with the pellet as with the milk version of the maze.

Spatial learning in an enclosed eight-arm radial maze in rats with sodium arsanilate-induced labyrinthectomies.

Bilateral vestibular dysfunction was induced in Long-Evans male rats (n = 7) by intratympanic injections of sodium arsanilate (30 mg/side). Control rats (n = 6) received isotonic saline. Animals were tested for labyrinthine integrity by measuring air-righting and contact-righting reflexes. Rats were reduced to 85% of free-feeding body weight and tested in an enclosed 8-arm radial maze (1 trial/day over 10 days). Labyrinthectomized animals made significantly more errors (p < .001) and, unlike the controls, showed no significant improvement on this measure over acquisition training. These rats also made significantly more (p = 0.018) sequential same arm reentries and fewer sequential adjacent arm entries (p < .01). These findings demonstrate that information obtained from the vestibular system is very important in spatial learning in the rat.

An examination of the relations between hippocampal long-term potentiation, kindling, afterdischarge, and place learning in the water maze.

Two approaches were used to study the relations between the acquisition of place learning in the Morris water maze and long-term potentiation (LTP), kindling, and afterdischarge (AD). In the first, the possibility of behavioral LTP in the dentate gyrus field potential evoked by stimulation of the perforant path was evaluated in rats that showed robust place learning in the water maze. There was no effect of place learning on the field potential, and field potential measures did not correlate with place learning acquisition measures. In the second approach, the effect of bilateral saturation of LTP on subsequent place learning in the water maze task, begun within 5 minutes of the last LTP session, was evaluated. The effect of kindled seizures evoked bilaterally from the perforant path, or of a single unilateral AD, on acquisition of the water maze task (begun within 10 minutes) were also evaluated. Bilateral LTP saturation did not affect place learning, and the bilateral LTP group learned as readily as controls. In contrast, the kindled and AD groups were severely impaired in their performance of the place learning task. A second day of training in the water maze without any further electrical stimulation indicated that these groups had acquired considerable information on the first day of maze training and were not distinguishable from controls on the second day of training. This indicated that the deficit in these groups on the first day of training was temporary and likely resulted from a temporary perturbation of normal brain function due to the seizures. The results indicate that bilateral saturation of LTP in the dentate gyrus does not affect place learning in the water maze. They also indicate that recent hippocampal seizures, but not kindling, disrupt place learning in this task.

Serotonin-dependent cerebral activation: effects of methiothepin and other serotonergic antagonists.

In scopolamine-treated (5.0 mg/kg, s.c.) rats hippocampal rhythmical slow activity (RSA) and neocortical low voltage fast activity (LVFA) occur only in close correlation with head movements, spontaneous changes in posture, or locomotion (Type I behavior). Previous work indicates that such scopolamine-resistant RSA and LVFA are dependent on ascending serotonergic projections. A test of 9 serotonergic antagonists (methiothepin; ritanserin; ketanserin; pizotifen; mianserin; pirenperone; ICS-205-930; metoclopramide; methysergide) showed that methiothepin produces a partial reduction in RSA and LVFA in scopolamine-treated rats, while the other antagonists are completely inactive over a wide range of doses. It may be that serotonergic cerebral activation depends on both 5-HT1 and 5-HT2 receptors.

Evidence for different neurochemical contributions to long-term potentiation and to kindling and kindling-induced potentiation: role of NMDA and urethane-sensitive mechanisms.

Long-term potentiation (LTP) and kindling share a number of features, and it has been suggested that LTP might constitute the cellular mechanism of kindling. This question was approached by assessing the effect of urethane anesthesia (0.75 or 1.5 g/kg) or blockade of NMDA receptors by local infusion of DL-2-amino-5-phosphonovaleric acid (APV; 7.5 micrograms) on LTP, partial kindling, and kindling-induced potentiation (KIP) in the perforant path-dentate gyrus circuit of the intact hooded rat. Urethane anesthesia attenuated but did not block LTP and completely blocked partial kindling and KIP. APV completely blocked LTP but did not block partial kindling or KIP in the unanesthetized rat. These results suggest that different neurochemical mechanisms can support LTP on the one hand, and kindling and KIP on the other. They are consistent with a contribution by NMDA-mediated LTP to kindling and KIP, but they indicate that this contribution is not crucial for kindling and KIP in this circuit.

Sodium arsanilate-induced vestibular dysfunction in meadow voles (Microtus pennsylvanicus): effects on posture, spontaneous locomotor activity and swimming behavior.

Vestibular dysfunction was chemically induced in male meadow voles (Microtus pennsylvanicus) by intratympanic injections (30 mg per side) of sodium arsanilate (atoxyl). The control group received intratympanic injections of isotonic saline. After a one-week recovery period the voles were behaviorally assayed for integrity of their labyrinthine systems. All subjects were tested for the presence of the air-righting reflex and body rotation-induced nystagmus. Three weeks later a multivariate assessment of spontaneous motor activity of the voles was carried out in the automated Digiscan Activity Monitor. In addition, the swimming behavior of the voles was examined. Voles with vestibular dysfunction exhibited pronounced postural abnormalities (head dorsiflexion), were not able to swim with their nose above the water for a 1 min test period, and displayed disorientation and thrashing movements. In the Digiscan activity test the atoxyl-treated voles displayed significantly more activity in the horizontal measures (Ps less than 0.01), including greater distance travelled per movement and greater speed of movements, relative to the control animals. The labyrinthectomized group also spent significantly (P less than 0.05) less time in vertical movements and exhibited significantly more time in stereotypic behavior (P less than 0.01), relative to controls. Atoxyl-treated voles also showed significantly less thigmotaxis (wall-hugging) than the control animals (P less than 0.01). In general, changes in spontaneous behavior observed in the sodium arsanilate-treated voles were consistent with the presence of postural and balance abnormalities and a redirecting of exploratory vertical movements toward horizontal locomotion to the extent that these animals were clearly hyperactive in this dimension. The multivariate behavioral assessment available in the Digiscan Activity Monitoring system, thus seems to be especially useful in the examination of behavioral components affected by vestibular dysfunction.

Hyperactivity, hyper-reactivity, and sensorimotor deficits induced by low doses of the N-methyl-D-aspartate non-competitive channel blocker MK801.

Three doses of MK801 (0.05 mg/kg, 0.3 mg/kg and 1.0 mg/kg) were given systemically to adult male rats, which were then tested on a battery of previously learned, reactive and spontaneous behaviors. Hyperactivity, hyper-reactivity, reductions in rearing behavior and deficits in tongue extension were found at the 0.05 mg/kg dose. Similar, but more severe results were found at the 0.3 mg/kg dose, with the addition of difficulties in climbing, balancing on a beam, and abnormalities in orienting to tactile stimuli. A number of tasks could not be performed at the 1.0 mg/kg dose including tongue extension, orienting, balancing on a beam, and climbing. Additionally, abnormal postures, gaits, and swimming behaviors were observed at this dose. These results characterize the behavioral effects of MK801 as a syndrome of hyperactivity, hyper-reactivity, and sensorimotor deficits. Evidence of this syndrome was present at all three doses, including the 0.05 mg/kg dose, which previously has been claimed to induce deficits similar to hippocampal lesions. Learning literature employing MK801 is discussed in the context of the behavioral deficits found in this study.