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Functional hemispheric lateralization is a basic principle of brain organization. In the auditory domain, the right auditory cortex (AC) determines the pitch direction of continuous auditory stimuli whereas the left AC discriminates gaps in these stimuli. The involved functional interactions between the two sides, mediated by commissural connections, are poorly understood. Here, we selectively disrupted the interhemispheric cross talk from the left to the right primary AC and vice versa using chromophore-targeted laser-induced apoptosis of the respective projection neurons, which make up 6–17% of all AC neurons in Layers III, V, and VI. Following photolysis, male gerbils were trained in a first experimental set to discriminate between rising and falling frequency-modulated (FM) tone sweeps. The acquisition of the task was significantly delayed in lesioned animals of either lesion direction. However, the final discrimination performance and hit rate was lowest for animals with left-side lesioned commissural neurons, demonstrating that also information from the left AC is relevant for FM direction learning. Photolysis after successful learning did not affect the retrieval of the learned task, indicating that the disruption during learning was not because of a general functional impairment. In a second experimental set, the gerbil's ability to detect and discriminate small silent gaps of varying length within FM sweeps was tested. This ability was also preserved after interhemispheric disruption. Taken together, interhemispheric communication between the left and right AC is important for the acquisition of FM tone direction learning but not for its retrieval and for gap detection and gap duration discrimination.SIGNIFICANCE STATEMENTHemispheric lateralization of neuronal functions such as speech and music processing in humans are common throughout the brain; however, the involved interhemispheric interactions are ill-defined. Here, we show that the selective photolytic disruption of auditory cortical commissural connections in rodents impairs the acquisition but not retrieval of a frequency-modulated tone direction discrimination task. The final discrimination performance and hit rate was lowest for animals with lesioned left-to-right-side projections; thus, although right auditory cortex is dominant, left auditory cortex is also relevant for learning this task. The detection and discrimination of small gaps within the tone sweeps remain intact, suggesting a pathway for the processing of these temporal structures, which could be independent from the lesioned interhemispheric cross talk.

We have previously shown that long-term potentiation (LTP) induces hippocampal IL-1β and IL-6 over-expression, and interfering their signalling either inhibits or supports, respectively, LTP maintenance. Consistently, blockade of endogenous IL-1 or IL-6 restricts or favours hippocampal-dependent memory, effects that were confirmed in genetically manipulated mice. Since cytokines are known for their high degree of mutual crosstalk, here we studied whether a network of cytokines with known neuromodulatory actions is activated during LTP and learning. We found that, besides IL-1β and IL-6, also IL-1 receptor antagonist (IL-1ra) and IL-18, but not TNFα are over-expressed during LTP maintenance in freely moving rats. The increased expression of these cytokines is causally related to an increase in synaptic strength since it was abrogated when LTP was interfered by blockade of NMDA-glutamate receptors. Likewise, IL-1 and IL-6 were found to be over-expressed in defined regions of the hippocampus during learning a hippocampus-dependent task. However, during learning, changes in IL-18 were restricted to the dorsal hippocampus, and no differences in TNFα and IL1-ra expression were noticed in the hippocampus. Noticeably, IL-1ra transcripts were significantly reduced in the prefrontal cortex. The relation between cytokine expression and learning was causal because such changes were not observed in animals from a pseudo-trained group that was subject to the same manipulation but could not learn the task. Taken together with previous studies, we conclude that activation of a cytokine network in the brain is a physiologic relevant phenomenon not only for LTP maintenance but also for certain types of learning.

Changes in synaptic efficacy underlying learning and memory processes are assumed to be associated with alterations of the protein composition of synapses. Here, we performed a quantitative proteomic screen to monitor changes in the synaptic proteome of four brain areas (auditory cortex, frontal cortex, hippocampus striatum) during auditory learning. Mice were trained in a shuttle box GO/NO-GO paradigm to discriminate between rising and falling frequency modulated tones to avoid mild electric foot shock. Control-treated mice received corresponding numbers of either the tones or the foot shocks. Six hours and 24 h later, the composition of a fraction enriched in synaptic cytomatrix-associated proteins was compared to that obtained from naive mice by quantitative mass spectrometry. In the synaptic protein fraction obtained from trained mice, the average percentage (±SEM) of downregulated proteins (59.9 ± 0.5%) exceeded that of upregulated proteins (23.5 ± 0.8%) in the brain regions studied. This effect was significantly smaller in foot shock (42.7 ± 0.6% down, 40.7 ± 1.0% up) and tone controls (43.9 ± 1.0% down, 39.7 ± 0.9% up). These data suggest that learning processes initially induce removal and/or degradation of proteins from presynaptic and postsynaptic cytoskeletal matrices before these structures can acquire a new, postlearning organisation. In silico analysis points to a general role of insulin-like signalling in this process.

The development of avoidance learning depends on dopamine release in forebrain regions. Previous studies indicated that rewarding brain stimulation facilitated two-way active avoidance learning. However, it is not clear whether the temporal relationship of brain stimulation to the training session (before, during or after) is important. To investigate the role of stimulation condition (no stimulation, self-stimulation only, or self-stimulation plus avoidance stimulation) and sequence of self-stimulation training (before or after avoidance training), we used a 3 × 2 factorial design, in which every level of stimulation was paired with every level of sequence for a total of 6 different groups. The results suggest that self-stimulation either before or after avoidance learning improved acquisition performance, but acquisition was maximal when stimulation was also given during acquisition trials. Importantly, the sequence of self-stimulation (before or after each acquisition session) was irrelevant to this beneficial effect. However, stimulation had no apparent effect on long-term retention when tested 10 days later under conditions of no stimulation, except that the performance of the group that had previously received avoidance-contingent stimulation deteriorated over the course of 60 trials. This may reflect frustration from the omission of expected reward. These results are relevant for optimizing brain stimulation to improve learning.

Two phenomena of auditory cortex activity have recently attracted attention, namely that the primary field can show different types of learning-related changes of sound representation and that during learning even this early auditory cortex is under strong multimodal influence. Based on neuronal recordings in animal auditory cortex during instrumental tasks, in this review we put forward the hypothesis that these two phenomena serve to derive the task-specific meaning of sounds by associative learning. To understand the implications of this tenet, it is helpful to realize how a behavioral meaning is usually derived for novel environmental sounds. For this purpose, associations with other sensory, e.g. visual, information are mandatory to develop a connection between a sound and its behaviorally relevant cause and/or the context of sound occurrence. This makes it plausible that in instrumental tasks various non-auditory sensory and procedural contingencies of sound generation become co-represented by neuronal firing in auditory cortex. Information related to reward or to avoidance of discomfort during task learning, that is essentially non-auditory, is also co-represented. The reinforcement influence points to the dopaminergic internal reward system, the local role of which for memory consolidation in auditory cortex is well-established. Thus, during a trial of task performance, the neuronal responses to the sounds are embedded in a sequence of representations of such non-auditory information. The embedded auditory responses show task-related modulations of auditory responses falling into types that correspond to three basic logical classifications that may be performed with a perceptual item, i.e. from simple detection to discrimination, and categorization. This hierarchy of classifications determine the semantic "same-different" relationships among sounds. Different cognitive classifications appear to be a consequence of learning task and lead to a recruitment of different excitatory and inhibitory mechanisms and to distinct spatiotemporal metrics of map activation to represent a sound. The described non-auditory firing and modulations of auditory responses suggest that auditory cortex, by collecting all necessary information, functions as a "semantic processor" deducing the task-specific meaning of sounds by learning.

Hemispheric asymmetries of speech and music processing might arise from more basic specializations of left and right auditory cortex (AC). It is not clear, however, whether such asymmetries are unique to humans, i.e., consequences of speech and music, or whether comparable lateralized AC functions exist in nonhuman animals, as evolutionary precursors. Here, we investigated the cortical lateralization of perception of linearly frequency-modulated (FM) tones in gerbils, a rodent species with human-like low-frequency hearing. Using a footshock-reinforced shuttle-box avoidance go/no-go procedure in a total of 178 gerbils, we found that ( i ) the discrimination of direction of continuous FM (rising versus falling sweeps, 250-ms duration) was impaired by right but not left AC lesions; ( ii ) the discrimination of direction of segmented FM (50-ms segments, 50-ms silent gaps, total duration 250 ms) was impaired by bilateral but not unilateral AC lesions; ( iii ) the discrimination of gap durations (10–30 ms) in segmented FM was impaired by left but not right AC lesions. AC lesions before and after training resulted in similar effects. Together, these experiments suggest that right and left AC, even in rodents, use different strategies in analyzing FM stimuli. Thus, the right AC, by using global cues, determines the direction of continuous and segmented FM but cannot discriminate gap durations. The left AC, by using local cues, discriminates gap durations and determines FM direction only when additional segmental information is available.

Background: Alcoholism is often accompanied by depression. It has been shown that deep electrical stimulation of the nucleus accumbens is effective in the treatment of alcoholism. Objective: Despite the promising results of clinical trials, the mechanisms underlying its effects are still unclear. To elucidate these mechanisms, valid animal models are needed. Methods: We investigated the effects of electrical stimulation of the nucleus accumbens shell (NAS) and nucleus accumbens core (NAC) on alcohol intake in bulbectomized rats. Bilateral removal of the olfactory bulbs (OBX) is considered a valid animal model of depression. Results: It was shown that electrical stimulation of the NAS with the described stimulus parameters significantly reduced voluntary ethanol intake in OBX rats. After the cessation of stimulation, this effect became insignificant. In contrast, stimulation of the NAC did not modify voluntary ethanol intake. In sham-bulbectomized animals, voluntary ethanol intake was negligible and ethanol consumption did not alter as a result of electrical stimulation of the NAC or NAS Conclusions: Our study underlines the relevance of the OBX model in the study of depression comorbid alcohol intake. Moreover, it might be useful in the study of the mechanisms underlying the clinical effectiveness of electrical stimulation of the NAS in the treatment of alcoholism.

Alzheimer's disease is a neurodegenerative disorder characterized by a loss of memory and spatial orientation. It is also reported that the dopamine system is affected. Dopamine plays a prominent role in motor functions, motivation, emotion, arousal and reward, and it is important for learning and memory. One model that represents characteristic hallmarks of Alzheimer's disease is the 5xFAD mouse model, in which parenchymal plaque load starts at 2months of age. Transgenic 5xFAD mice show the first behavioral deficits at 6months, which are evident at 9months of age. In this study, we investigated the pharmacological influence of methylphenidate (MPH) on behavioral deficits of 5xFAD mice. Using a battery of behavioral tests, we observed no influence of MPH on anxiety in the elevated plus maze, whereas the locomotion and explorative activity in the open field was increased in transgenic and non-transgenic 5xFAD mice after the application of MPH. Further MPH inhibits habituation in the open field in healthy 5xFAD littermates after the application of 10mg/kg MPH. On the other hand, 10mg/kg MPH improved spatial memory in 6-month-old transgenic 5xFAD males, i.e., at a time point when deficits start to occur. However, in 9-month-old transgenic mice, MPH did not improve persisting learning and memory deficits. We concluded that MPH might improve the non-cognitive, apathy-like behavior (indicated by a reduced exploration), but it has no influence on sustained Alzheimer typical learning and memory deficits.

Summary: Purpose: The aim of the study was to define sleep disturbances in pentylenetetrazole (PTZ)-kindled rats and to explore the effects of the nootropic drug piracetam (Pir; 100 mg/kg) and the noncompetitive N-methyl-d-aspartate (NMDA)-antagonist MK-801 (0.3 mg/kg), which normalized learning performance in PTZ-kindled rats, on altered sleep parameters. Methods: This is the first report showing a significant reduction in paradoxical sleep (PS) as a consequence of PTZ kindling. A correlation analysis revealed a significant correlation between seizure severity and PS deficit. Results: Pir did not interfere with seizure severity, and the substance did not ameliorate the PS deficit. However, the substance disconnected the correlation between seizure severity and PS deficit. MK-801, which reduced the severity of kindled seizures, counteracted the PS deficit efficaciously. Conclusions: The results suggest that seizure severity and alterations in sleep architecture are two factors in the comprehensive network underlying learning impairments associated with epilepsy. Considering the results obtained in the experiments with Pir, reduction of seizure severity does not guarantee the reduction of impairments in the domain of learning.

The influence of early experience and strain differences on auditory discrimination learning, open field behaviour and brain size was investigated in wild-type Mongolian gerbils (strain Ugoe:MU95) raised in the wild (wild F-0) or in the laboratory (wild F-1) and in domesticated Laboratory Gerbils (LAB). Adult males were conditioned for 10 days in a shuttle box go/no-go paradigm to discriminate two frequency-modulated tones. Significant learning was established within 5 days in wild F-0 and within 3 days in wild F-1 and LAB. Spontaneous jumps in the shuttle box (inter-trial crossings) were frequently seen in wild F-0 and F-1, but rarely in LAB. All groups exhibited nearly the same ability to remember after 2 weeks without training. In the open field test applied on 5 consecutive days, no differences in locomotion patterns and inner field preferences were found. Rearing frequency decreased over 5 days in wild gerbils. Running distances (4-6m/min) were similar in wild F-0 and LAB, but higher in wild F-1. The ratio of brain size to body weight did not differ between wild F-0 and F-1, but was 17.1% lower in LAB. Correspondingly high brain weights in wild F-1 and F-0 support our domestication hypothesis and negate any serious effect of early experience or captivity on brain size in Mongolian gerbils. In contrast, wild F-1 raised in the laboratory show a rapid improvement in learning performance, indicating that early experience rather that genetic differences between strains affect shuttle box discrimination learning in gerbils.

Group I metabotropic glutamate receptors (mGluRs) have been implicated in learning and memory formation. Recent findings indicate an important function of the group I mGluR subtype 5. Here, we used the Y-maze spatial alternation task and examined whether enhancement of intrinsic mGluR5 activity immediately after learning, i.e. during a critical period for memory consolidation, would have any consequences on long-term memory retention in rats. Intracerebroventricular application of the allosteric mGluR5 potentiator DFB (3,3'-difluorobenzaldazine) resulted in a marked improvement in spatial alternation retention when it was tested 24 h after training. The promnesic effect increased with the difficulty of the task and was apparently due to a substantial enhancement of consolidation. The applied dose of DFB did not cause behavioral changes in the open field, and was devoid of structural side-effects as evaluated by immunohistochemical examination. Our results suggest an important function of post-training mGluR5 activation in some types of hippocampus-dependent spatial learning.

Growing evidence supports the idea that sleep following learning is critically involved in memory formation. Recent studies suggest that information acquired during waking is reactivated and possibly consolidated during subsequent sleep, especially during rapid-eye movement (REM) or paradoxical sleep (PS). Critical reviews, however, have questioned PS and memory relationships, particularly because of shortcomings of the PS deprivation paradigm applied in many studies. Therefore, in the present study we used an opposite strategy, i.e. we investigated the effects of PS enhancement on memory retention. In three experiments, we found that selective PS enhancement, induced by different procedures after discrimination training in rats, results in increased retention tested 24 h later. Moreover, calculated in all animals (n = 61), there was a highly significant correlation between post-training PS values and retention scores. Our results suggest that an experimentally induced increase of PS after learning facilitates memory consolidation.

Differential conditioning of Mongolian gerbils to linearly frequency-modulated tones (FM) has recently received experimental attention. In the study of the role of cerebral protein synthesis for FM discrimination memory, gerbils received post-training bilateral injections of anisomycin into the auditory cortex under light halothane anesthesia. Compared with saline-treated controls, anisomycin-treated gerbils showed a discrimination decrement during the subsequent three days of training. They markedly improved their performance within training sessions, but started each session at low levels. When repeatedly trained gerbils received post-session injections of anisomycin, discrimination performance during subsequent sessions was similar to the pre-injection performance, indicating that retention, retrieval, reconsolidation, and expression of the established reaction were not affected. However, the improvement of a partially established discrimination reaction was impaired after this treatment. Intracortical injections of emetine confirmed this finding. Neither drug affected FM discrimination learning when given several days before the initial training. Our results suggest that protein-synthesis inhibitors applied to the auditory cortex of gerbils during the post-acquisition phase interfered with learning and memory-related aspects of FM processing. The resulting deficit was evident for a number of post-injection training days. This effect was probably due to impaired consolidation, i.e., processes required for long-term stabilization or retrieval of the memory trace while leaving short-term memory intact.

Many animal and human subjects can learn to avoid punishment or noxious stimuli by exploiting the sensory cues predicting them. In cue-signaled active avoidance (AA) learning, subjects first learn about the predictive properties of cues and subsequently learn a behavioral strategy of an avoidance response (e.g., crossing a hurdle that divides a two-compartment cage in order to avoid a mild but unpleasant footshock). AA learning develops with fear reduction as an intervening variable (Mowrer and Lamoreaux, 1946; Miller, 1948). If execution of avoidance action occurs on the pursuit of seeking safety, an overlap of recruitments of neurocircuitry essential for reward processing and for avoidance can be expected on the basis of two-process theory. Recent insights from two-way AA (2WAA) studies, which integrate both Pavlovian and instrumental components, provide strong evidence for the recruitment of emotional circuitry centered on the amygdala and motivational circuitry centered around midbrain dopaminergic structures. In this review, we address the following: (1) the role of emotional neurocircuitry in the formation of AA, (2) the involvement of reward circuitry and its input-output pathways on AA, and (3) the possible serial and parallel processing within and between these circuitries.

Transgenic animal models of Alzheimer's disease (AD) are widely used to investigate mechanisms of pathophysiology and cognitive dysfunctions. A model with a very early development of parenchymal plaque load at the age of 2months is the 5xFAD mouse (Tg6799, Oakley et al. 2006). These 5xFAD mice over-express both human amyloid precursor protein (APP) and human presenilin 1 (PS1). Mice from this line have a high APP expression correlating with a high burden and an accelerated accumulation of the 42 amino acid species of amyloid-β (Aβ). The aim of this study was the behavioral and functional investigations of 5xFAD males because in most studies females of this strain were characterized. In comparison to literature of transgenic 5xFAD females, transgenic 5xFAD males showed decreased anxiety in the elevated plus maze, reduced locomotion and exploration in the open field and disturbances in learning performance in the Morris water maze starting at 9months of age. Electroencephalogram (EEG) recordings on 6month old transgenic mice revealed a decrease of delta, theta, alpha, beta and gamma frequency bands whereas the subdelta frequency was increased. EEG recordings during sleep showed a reduction of rapid eye movement sleep in relation to the amount of total sleep. Thus, 5xFAD males develop early functional disturbances and subsequently behavioral deficits and therefore they are a good mouse model for studying Alzheimer's disease.

It is commonly assumed that cortical activity in non-rapid eye movement sleep (NREMS) is spatially homogeneous on the mesoscopic scale. This is partly due to the limited observational scope of common metabolic or imaging methods in sleep. We used the recently developed technique of thallium-autometallography (TlAMG) to visualize mesoscopic patterns of activity in the sleeping cortex with single-cell resolution. We intravenously injected rats with the lipophilic chelate complex thallium diethyldithiocarbamate (TlDDC) during spontaneously occurring periods of NREMS and mapped the patterns of neuronal uptake of the potassium (K+) probe thallium (Tl+). Using this method, we show that cortical activity patterns are not spatially homogeneous during discrete 5-min episodes of NREMS in unrestrained rats—rather, they are complex and spatially diverse. Along with a relative predominance of infragranular layer activation, we find pronounced differences in metabolic activity of neighboring neuronal assemblies, an observation which lends support to the emerging paradigm that sleep is a distributed process with regulation on the local scale. Electronic supplementary material The online version of this article (doi:10.1007/s00429-014-0867-9) contains supplementary material, which is available to authorized users.

This study examines the role of auditory cortex in the Mongolian gerbil in differential conditioning to pure tones and to linearly frequency-modulated (FM) tones by analyzing the effects of bilateral auditory cortex ablation. Learning behavior and performance were studied in a GO/NO-GO task aiming at avoidance of a mild foot shock by crossing a hurdle in a two-way shuttle box. Hurdle crossing as the conditioned response to the reinforced stimulus (CR+), as false alarm in response to the unreinforced stimulus (CR−), intertrial activity, and reaction times were monitored. The analysis revealed no effects of lesion on pure tone discrimination but impairment of FM tone discrimination. In the latter case lesion effects were dependent on timing of lesion relative to FM tone discrimination training. Lesions before training in naive animals led to a reduced CR+ rate and had no effect on CR− rate. Lesions in pretrained animals led to an increased CR− rate without effects on the CR+ rate. The results suggest that auditory cortex plays a more critical role in discrimination of FM tones than in discrimination of pure tones. The different lesion effects on FM tone discrimination before and after training are compatible with both the hypothesis of a purely sensory deficit in FM tone processing and the hypothesis of a differential involvement of auditory cortex in acquisition and retention, respectively.

Metabotropic glutamate receptors (mGluRs) are postulated to play a role in long-term potentiation and in learning and memory-formation. Previously, we found that the group I/II mGluR antagonist, (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG), blocks Y-maze spatial alternation learning. In this study, we tested the group I mGluR antagonist (S)4-carboxyphenylglycine (4-CPG) in comparison with MCPG using the same behavioural paradigm. Male Wistar rats were intracerebroventricularly injected with either 29 microg 4-CPG or 209 microg MCPG, 30 min prior to learning. Neither 4-CPG nor MCPG had an effect on spatial alternation performance in the training session. In the memory-retention test 24 h later, however, both the 4-CPG- and the MCPG-treated animals were strongly impaired compared with NaCl-injected control rats. These results suggest a particular importance of group I mGluRs in spatial memory-formation and indicate that MCPG effects found in previous learning experiments were predominantly due to an action at group I mGluRs.

Substances acting upon rapid eye movement (REM) sleep or paradoxical sleep (PS) can affect the number and/or the duration of PS episodes. In the present study, we investigated the effects of the proopiomelanocortin-derived peptide CLIP (corticotropin-like intermediate lobe peptide, ACTH 18-39) and its N-terminal fragments ACTH 18-24 and ACTH 20-24 on the duration of PS episodes in rats. Intracerebroventricular injection of ACTH 20-24 caused a pronounced prolongation of PS episodes (up to 7 min duration, never seen under baseline conditions), whereas ACTH 18-24 acted in a similar way but without reaching statistical significance. We suggest that short N-terminal CLIP fragment(s) may represent endogenous hypnogenic factor(s) involved in the regulation of paradoxical sleep.

The lateral habenula (LHb) is an epithalamic structure involved in signaling reward omission and aversive stimuli, and it inhibits dopaminergic neurons during motivated behavior. Less is known about LHb involvement in the acquisition and retrieval of avoidance learning. Our previous studies indicated that brief electrical stimulation of the LHb, time-locked to the avoidance of aversive footshock (presumably during the positive affective “relief” state that occurs when an aversive outcome is averted), inhibited the acquisition of avoidance learning. In the present study, we used the same paradigm to investigate different frequencies of LHb stimulation. The effect of 20 Hz vs. 50 Hz vs. 100 Hz stimulation was investigated during two phases, either during acquisition or retrieval in Mongolian gerbils. The results indicated that 50 Hz, but not 20 Hz, was sufficient to produce a long-term impairment in avoidance learning, and was somewhat more effective than 100 Hz in this regard. None of the stimulation parameters led to any effects on retrieval of avoidance learning, nor did they affect general motor activity. This suggests that, at frequencies in excess of the observed tonic firing rates of LHb neurons (>1–20 Hz), LHb stimulation may serve to interrupt the consolidation of new avoidance memories. However, these stimulation parameters are not capable of modifying avoidance memories that have already undergone extensive consolidation.

Previous studies have shown that spatial memory retention is affected by the metabotropic glutamate receptor (mGluR) influencing agents (R,S)-alpha-methyl-4-carboxyphenylglycine (MCPG) and trans-azetidine-2,4-dicarboxylic acid (tADA). In the present investigation we examined whether the mGluR antagonist MCPG (20 mM and 200 mM/5 microliters, respectively) and the agonist tADA (20 mM/5 microliters) have other behavioural effects using the open field test on two successive days. Only minor effects of MCPG (decrease of crossings during the 1st min on day 1) and tADA (increase of rearings on both days) were found. These results suggest that memory influencing doses of MCPG and tADA have no or only little behavioural effects in the open field situation.

We examined the effects of both the metabotropic glutamate receptor (mGluR) antagonist MCPG and the agonist tADA in two behavioral paradigms in rats: (1) brightness discrimination and (2) spatial alternation. Compounds were applied intracerebroventricularly at different times, either 30 min prior to training or immediately after training, and rats were tested for retention 24 hr later in the same paradigms. Both MCPG and tADA caused amnesia in the spatial alternation test, when applied pretraining, but no effect was obtained in the brightness discrimination paradigm. Drug-induced amnesia was shown not to be attributable to state-dependent effects of MCPG or tADA. Moreover, the memory inhibiting effect of MCPG was dose dependent, with a low dose (20 mM/5 ml) having no effect on learning and memory and a 10 times higher concentration (200 mM/5 ml) causing complete amnesia. Application of both saline and MCPG immediately post-training prevented memory formation, which may be attributable to an interference by the injection procedure with the process of memory formation. The mGluR agonist tADA, however, facilitated memory formation in the spatial alternation task, when injected immediately after training. Post-training application of the compounds had no effect on retention in the brightness discrimination task. On the basis of these data we conclude that (1) mGluRs are of particular importance for spatial learning and play no role in visual discrimination; (2) both the block and the activation of mGluRs inhibit spatial learning, suggesting that saturated activation prevents further modulation of mGluRs, which may be required during learning or memory formation; and (3) mGluR agonist tADA may be memory facilitating when applied after training, thus enhancing the establishment of the memory trace.

Learning from punishment is a powerful means for behavioral adaptation with high relevance for various mechanisms of self-protection. Several studies have explored the contribution of released dopamine (DA) or responses of DA neurons on reward seeking using rewards such as food, water, and sex. Phasic DA signals evoked by rewards or conditioned reward predictors are well documented, as are modulations of these signals by such parameters as reward magnitude, probability, and deviation of actually occurring from expected rewards. Less attention has been paid to DA neuron firing and DA release in response to aversive stimuli, and the prediction and avoidance of punishment. In this review, we first focus on DA changes in response to aversive stimuli as measured by microdialysis and voltammetry followed by the change in electrophysiological signatures by aversive stimuli and fearful events. We subsequently focus on the role of DA and effect of DA manipulations on signaled avoidance learning, which consists of learning the significance of a warning cue through Pavlovian associations and the execution of an instrumental avoidance response. We present a coherent framework utilizing the data on microdialysis, voltammetry, electrophysiological recording, electrical brain stimulation, and behavioral analysis. We end by outlining current gaps in the literature and proposing future directions aimed at incorporating technical and conceptual progress to understand the involvement of reward circuit on punishment based decisions.

Upon infection with the obligate intracellular parasite Toxoplasma gondii, fast replicating tachyzoites infect a broad spectrum of host cells including neurons. Under the pressure of the immune response, tachyzoites convert into slow-replicating bradyzoites, which persist as cysts in neurons. Currently, it is unclear whether T. gondii alters the functional activity of neurons, which may contribute to altered behaviour of T. gondii-infected mice and men. In the present study we demonstrate that upon oral infection with T. gondii cysts, chronically infected BALB/c mice lost over time their natural fear against cat urine which was paralleled by the persistence of the parasite in brain regions affecting behaviour and odor perception. Detailed immunohistochemistry showed that in infected neurons not only parasitic cysts but also the host cell cytoplasm and some axons stained positive for Toxoplasma antigen suggesting that parasitic proteins might directly interfere with neuronal function. In fact, in vitro live cell calcium (Ca(2+)) imaging studies revealed that tachyzoites actively manipulated Ca(2+) signalling upon glutamate stimulation leading either to hyper- or hypo-responsive neurons. Experiments with the endoplasmatic reticulum Ca(2+) uptake inhibitor thapsigargin indicate that tachyzoites deplete Ca(2+) stores in the endoplasmatic reticulum. Furthermore in vivo studies revealed that the activity-dependent uptake of the potassium analogue thallium was reduced in cyst harbouring neurons indicating their functional impairment. The percentage of non-functional neurons increased over time In conclusion, both bradyzoites and tachyzoites functionally silence infected neurons, which may significantly contribute to the altered behaviour of the host.

The effects of the POMC-derived peptide CLIP [corticotropin-like intermediate lobe peptide; ACTH(18-39)] and its shorter fragments ACTH(25-39), ACTH(18-24), and ACTH(20-24) on sleep were investigated in rats housed under normal 12-h light/12-h dark conditions (0600 light on). CLIP (10 ng) or equimolar doses of CLIP fragments, respectively, were injected intracerebroventricularly immediately before the 8-h recording period (0800-1600). It was found that paradoxical sleep (PS) was increased by CLIP (+20%) as well as by the N-terminal CLIP fragment ACTH(18-24) (+18%) and by the pentapeptide ACTH(20-24) (+25%), whereas the C-terminal fragment ACTH(25-39) was ineffective. Slow-wave sleep (SWS) was not influenced. These results clearly demonstrate that CLIP and its N-terminal fragments have selective PS-enhancing effects. CLIP and/or CLIP partial sequences are possible candidates for endogenous PS-inducing peptides involved in the physiological regulation of paradoxical sleep.

The effects of the peptide [des-Tyr- d -Phe 3 ]beta-casomorphin(2–5) (BCH-325; Pro- d -Phe-Pro-Gly; 2.27, 22.7, and 227 μg/kg) on cortical EEG power spectra in rats were studied compared to those of other psychotropic drugs, including diazepam, amitriptyline, haloperidol, and amphetamine. All drugs were injected IP, and cortical EEG power spectra were recorded from freely moving rats for 2 h postinjection. Administration of 22.7 and 227 μg/kg BCH-325 resulted in an increase in alpha-2 and beta-1 frequency bands and a decrease in slower frequencies (delta, theta). Our findings show that the effects of BCH-325 on cortical EEG power spectra differ from those of other psychotropic drugs.

Transient global ischaemia induces cell death in the CA1 layer of the hippocampus. To evaluate the functional consequences, we performed context-dependent fear conditioning. Ischaemia was induced by 2-vessel-occlusion (2VO) in gerbils. On day 6 post ischaemia or sham procedures (in control group) gerbils were placed in a test chamber and after 3 min adaption time exposed to foot-shocks (training session). On the next day the animals were placed in the same test chamber without foot-shocks (test session). As a parameter for memory performance we used the standard method of measuring the total freezing time via a cumulative time-sampling procedure during the test session. We found a significant longer total freezing time in control animals than in ischaemic animals. In addition, however, we applied a more detailed analysis of (i) quantifying the number of freezing bouts, (ii) the average duration of single freezing bouts, (iii) the activity pattern during the training and test situation and (iv) we differentially evaluated all the single time segments of the experiment. These analyses revealed that although maintenance of freezing (duration of freezing bout) was significantly lower in ischaemic animals compared to controls, the initiation of freezing (number of freezing bouts) was not significantly different between the two groups during the test session. The activity scores of ischaemic and non-ischaemic gerbils were similar during the adaption time of the training session. The foot-shock, however, induced a significantly different pattern of behaviour in the ischaemic animals, which was selectively reproduced during the test session. In conclusion, ischaemic gerbils reacted to a fearsome thread with a behavioural pattern different from unlesioned animals and they revealed this specific foot-shock induced behaviour again during the test session. This indicated that CA1 hippocampal death did not interrupt memory performance but changed expression of fear. Therefore, measuring duration of freezing and the activity score seems to be not applicable for quantitative comparisons of memory deficits after 2VO in gerbils in a context-dependent fear conditioning task. Our results indicate, however, that initiation of freezing (number of freezing bouts) may be a more suitable parameter comparing gerbils with and without CA1 damage.

Several studies suggest an opponent functional relationship between the lateral habenula (LHb) and the ventral tegmental area (VTA). Previous work has linked LHb activation to the inhibition of dopaminergic neurons during loss of reward, as well as to deficits in escape and avoidance learning. We hypothesized that a dopamine signal might underlie the negative reinforcement of avoidance responses and that LHb activation could block this signal and thereby cause avoidance deficits. To test this idea, we implanted stimulating electrodes in either the VTA or LHb of gerbils engaged in two-way active avoidance learning, a task that shows learning-associated dopamine changes and that is acquired faster following LHb lesions. We delivered brief electrical brain stimulation whenever the animal performed a correct response, i.e., when the successful avoidance of foot shock was hypothesized to trigger an intrinsic reward signal. During the acquisition phase, VTA stimulation improved avoidance performance, while LHb stimulation impaired it. VTA stimulation appeared to improve both acquisition and asymptotic performance of the avoidance response, as VTA-stimulated animals reached above-normal performance but reverted to normal responding when stimulation was discontinued. The effects of LHb stimulation during avoidance acquisition were long lasting and persisted even after stimulation was discontinued. However, when given after successful acquisition of avoidance behavior, LHb stimulation had no effect, indicating that LHb stimulation specifically impaired avoidance acquisition without affecting memory retrieval or motivation or ability to perform the avoidance response. These results demonstrate opponent roles of LHb and VTA during acquisition but not during retrieval of avoidance learning.

Learned changes in behavior can be elicited by either appetitive or aversive reinforcers. It is, however, not clear whether the two types of motivation, (approaching appetitive stimuli and avoiding aversive stimuli) drive learning in the same or different ways, nor is their interaction understood in situations where the two types are combined in a single experiment. To investigate this question we have developed a novel learning paradigm for Mongolian gerbils, which not only allows rewards and punishments to be presented in isolation or in combination with each other, but also can use these opposite reinforcers to drive the same learned behavior. Specifically, we studied learning of tone-conditioned hurdle crossing in a shuttle box driven by either an appetitive reinforcer (brain stimulation reward) or an aversive reinforcer (electrical footshock), or by a combination of both. Combination of the two reinforcers potentiated speed of acquisition, led to maximum possible performance, and delayed extinction as compared to either reinforcer alone. Additional experiments, using partial reinforcement protocols and experiments in which one of the reinforcers was omitted after the animals had been previously trained with the combination of both reinforcers, indicated that appetitive and aversive reinforcers operated together but acted in different ways: in this particular experimental context, punishment appeared to be more effective for initial acquisition and reward more effective to maintain a high level of conditioned responses (CRs). The results imply that learning mechanisms in problem solving were maximally effective when the initial punishment of mistakes was combined with the subsequent rewarding of correct performance.

Brain extract was obtained from whole brains of donor rats following four days of paradoxical sleep deprivation (PSD). Intraperitoneal injection of this brain extract in normal (i.e., not pretreated) recipient rats led to a significant increase of paradoxical sleep (PS) which was beginning at the third hour postinjection and still present on the day after treatment. Both PS episode number and PS episode duration were increased by the PSD extract, whereas slow-wave sleep was not influenced. Brain extract of nondeprived control rats, on the other hand, had no significant effects. In the present experiments, an extract volume obtained from two donor brains was transferred to one recipient. Compared to our earlier investigations (one donor brain/one recipient) this higher "dose" of PSD extract exerted a more pronounced and prolonged effect. These results support the idea that some PS-inducing factor(s) accumulating in the brain during PS deprivation may be involved in the regulation of paradoxical sleep.

The aim of the study was to define sleep disturbances in pentylenetetrazole (PTZ)-kindled rats and to explore the effects of the nootropic drug piracetam (Pir; 100 mg/kg) and the noncompetitive N-methyl-D-aspartate (NMDA)-antagonist MK-801 (0.3 mg/kg), which normalized learning performance in PTZ-kindled rats, on altered sleep parameters.This is the first report showing a significant reduction in paradoxical sleep (PS) as a consequence of PTZ kindling. A correlation analysis revealed a significant correlation between seizure severity and PS deficit.Pir did not interfere with seizure severity, and the substance did not ameliorate the PS deficit. However, the substance disconnected the correlation between seizure severity and PS deficit. MK-801, which reduced the severity of kindled seizures, counteracted the PS deficit efficaciously.The results suggest that seizure severity and alterations in sleep architecture are two factors in the comprehensive network underlying learning impairments associated with epilepsy. Considering the results obtained in the experiments with Pir, reduction of seizure severity does not guarantee the reduction of impairments in the domain of learning.

Bilateral rapid-rate transcranial magnetic stimulation (rTMS) of gerbil auditory cortex with a miniature coil device was used to study short-term and long-term effects on discrimination learning of frequency-modulated tones. We found previously that directional discrimination of frequency modulation (rising vs. falling) relies on auditory cortex processing and that formation of its memory depends on local protein synthesis. Here we show that, during training over 5 days, certain rTMS regimes contingent on training had differential effects on the time course of learning. When rTMS was applied several times per day, i.e. four blocks of 5 min rTMS each followed 5 min later by a 3-min training block and 15-min intervals between these blocks (experiment A), animals reached a high discrimination performance more slowly over 5 days than did controls. When rTMS preceded only the first two of four training blocks (experiment B), or when prolonged rTMS (20 min) preceded only the first block, or when blocks of experiment A had longer intervals (experiments C and D), no significant day-to-day effects were found. However, in experiment A, and to some extent in experiment B, rTMS reduced the within-session discrimination performance. Nevertheless the animals learned, as demonstrated by a higher performance the next day. Thus, our results indicate that rTMS treatments accumulate over a day but not strongly over successive days. We suggest that rTMS of sensory cortex, as used in our study, affects short-term memory but not long-term memory formation.

Our previous studies have shown, in vivo and in vitro , that long-term potentiation (LTP) induces an NMDA receptor-dependent expression of IL-1β and IL-6 in the hippocampus. Blockade of the receptors for these cytokines either decreases (IL-1) or supports (IL-6) LTP maintenance, indicating the physiological relevance of their effects. Consistently, interference with IL-1 or IL-6 signalling also restricts or favours, respectively, hippocampus-dependent learning. The question that arises is whether brain-borne cytokines that interact with each other affect learning and memory consolidation just because they have a tonic, permissive effect or because their production increases during learning and are therefore part of the neuro-chemical changes involved in this process, as it occurs during LTP. Here we provide evidence that, besides IL-1β and IL-6, the endogenous IL-1 receptor antagonist (IL-1ra) and IL-18, but not TNF α , are produced during LTP in freely moving rats. Furthermore, we found that IL-1β and IL-6 genes are over-expressed in different hippocampal regions soon after learning a hippocampus-dependent alternation task. Restricted changes in IL-18 and no differences in TNF α and IL1-ra expression were noticed in the hippocampus during this learning process, but IL-1ra transcripts were significantly reduced in the prefrontal cortex. These effects were not noticed in pseudo-trained rats that could not learn the task. Taken together with previous studies, we conclude that activation of a cytokine network in the brain is a physiologic relevant condition not only for LTP maintenance but also for the consolidation of the learning process.

It is known that proinflammatory cytokines such as interleukin-6 (IL-6) are expressed in the central nervous system (CNS) during disease conditions and affect several brain functions including memory and learning. In contrast to these effects observed during pathological conditions, here we describe a physiological function of IL-6 in the “healthy” brain in synaptic plasticity and memory consolidation. During long-term potentiation (LTP) in vitro and in freely moving rats, IL-6 gene expression in the hippocampus was substantially increased. This increase was long lasting, specific to potentiation, and was prevented by inhibition of N-methyl-Daspartate receptors with (±)-2-amino-5-phosphonopentanoic acid (AP-5). Blockade of endogenous IL-6 by application of a neutralizing anti-IL6 antibody 90 min after tetanus caused a remarkable prolongation of LTP. Consistently, blockade of endogenous IL-6, 90 min after hippocampus-dependent spatial alternation learning resulted in a significant improvement of long-term memory. In view of the suggested role of LTP in memory formation, these data implicate IL-6 in the mechanisms controlling the kinetics and amount of information storage. Fil: Balschun, D.. Leibniz Institute for Neurobiology; Alemania Fil: Wetzel, W.. Leibniz Institute for Neurobiology; Alemania Fil: del Rey, A.. Philipps University Marburg; Alemania Fil: Pitossi, Fernando Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Schneider, Heloisa. Philipps University Marburg; Alemania Fil: Zuschratter, W.. Leibniz Institute for Neurobiology; Alemania Fil: Besedovsky, H. O.. Philipps University Marburg; Alemania

As demonstrated recently, mGluRs are involved in some forms of learning. We thus investigated the effect of tADA (trans-azetidine-2,4-dicarboxylic acid) applied intracerebroventricularly prior to learning a spatial alternation paradigm. Compared to controls, tADA treated animals were amnesic when tested for retention 24 hr after training. Effects of state-dependency were excluded. These data and our earlier work indicate that both mGluR agonists and antagonists can have memory-disrupting effects.

Repeated separation from the family during very early stages of life is a stressful emotional experience which induces a variety of neuronal and synaptic changes in limbic cortical areas that may be related to behavioral alterations. First, we investigated whether repeated parental separation and handling, without separation from the family, leads to altered spontaneous exploratory behavior in a novel environment (open field test) in 8-day-old Octodon degus. Second, we tested whether the parentally deprived and handled animals display different stimulus-evoked exploratory behaviors in a modified open field version, in which a positive emotional stimulus, the maternal call, was presented. In the open field test a significant influence of previous emotional experience was found for the parameters of running, rearing, and vocalization. Parentally deprived degus displayed increased horizontal (running) and vertical (rearing) motoric activities, but decreased vocalization, compared to normal and handled controls. The presentation of maternal vocalizations significantly modified running, vocalization, and grooming activities, which in the case of running activity was dependent on previous emotional experience. Both deprivation-induced locomotor hyperactivity together with the reduced behavioral response towards a familiar acoustic emotional signal are similar to behavioral disturbances observed in human attachment disorders.

Metabotropic glutamate receptors (mGluRs) have been implicated in long-term potentiation and in learning and memory formation. In this study, we tested the effects of group I mGluR inhibition on synaptic plasticity and learning of rats at different levels of organization (1) in the hippocampal slice preparation; (2) in freely moving animals implanted with chronic hippocampal electrodes; and (3) in different spatial learning paradigms. To allow a direct comparison of the effects obtained the same doses were used in all paradigms. Bath-application of the selective group I mGluR antagonist (S)4-carboxyphenylglycine (4-CPG) impaired a decremental long-term potentiation (LTP) induced by a weak tetanization paradigm, but failed to affect a robust LTP generated by strong tetanization. In contrast, 4-CPG impaired a robust LTP in freely moving animals if applied 30 min before tetanization. The same dose of 4-CPG only impeded spatial learning mildly in the eight-arm radial maze and had no effect on a simple configuration of the Y-maze spatial alternation task. In the more difficult configuration of this task, however, 4-CPG caused complete amnesia. The lack of state-dependent 4-CPG actions and the absence of any 4-CPG effects in the open-field test classify the obtained retention deficit as a selective impairment of memory storage. Our results indicate a specific role of group I mGluRs in certain types of synaptic plasticity and of spatial learning.

Mongolian gerbils (Meriones unguiculatus) were trained in a shuttle box to discriminate the direction in frequency-modulated tones (FM). Whereas control animals easily acquired FM discrimination, animals with auditory cortex lesion on the right side showed considerable difficulties in learning this task. The discrimination performance of gerbils with left auditory cortex lesion, however, was not different from controls. This study, suggesting that the right auditory cortex plays a dominant role in FM discrimination learning in gerbils, describes a useful animal model for investigation of the basic mechanisms underlying hemispheric asymmetries in auditory perception.

Discrimination of the direction of linearly frequency-modulated tones (FMs) was investigated in adult Mongolian gerbils (Meriones unguiculatus) using a footshock motivated shuttle box avoidance go/no go procedure. Symmetric pairs of FMs with frequency linearly increasing with time (ascending FMs) and with frequency linearly decreasing with time (descending FMs) were used as conditioned stimuli, CS+ and CS−, respectively. Stimuli were presented in randomized order in daily sessions over a period of several months. After a number of sessions, the set of conditioned stimuli was changed with respect to frequency range, steepness of modulation and duration. In experiment 1, we observed that gerbils could discriminate between the ascending 2–4 kHz CS+ and the descending 4–2 kHz CS− after a training period of 10–15 days. In experiment 2, we used FM pairs of six other frequency ranges in successive sessions (6–13; 1–2; 13–25; 0.5–1; 3–6; 0.25–0.5 kHz). We found that in the final session the last FM pair (0.25–0.5 kHz) was discriminated already after 3–4 days. Experiment 3 showed that the animals were able to discriminate five of the FM pairs learned in the separate sessions of experiment 2 (i.e. 10 different stimuli) when they were given in randomized order during one training session. In experiment 4, novel FM pairs (not heard before) and familiar FM pairs (trained in experiments 1–3) were presented within one session. It was found that, except for FMs of very short duration and small frequency range, novel FMs were discriminated according to their modulation direction. These results show that Mongolian gerbils are able to discriminate FM tones by modulation direction and, after familiarization with a number of different FM pairs, transfer the ascending–descending concept to stimuli not heard before.

1. Neuronal plasticity has been suggested to be the physical substrate for changes underlying the expression of memory. One model which has attracted wide attention as a possible candidate of such neuronal plasticity is long-term potentiation (LTP), mainly investigated in the hippocampus of rodents. Moreover, various processes with different time constants may underlie LTP, and these phases show striking correspondence to different phases of memory. 2. Pharmacological evidence strongly implicates that the neurotransmitter glutamate plays a major role in LTP. Although the involvement of ionotropic glutamate receptors has been proven, the role of the newly discovered metabotropic glutamate receptors is still uncertain. 3. Metabotropic glutamate receptors (mGluRs) comprise a whole family with currently eight members grouped into three classes according to their amino acid sequence identity and pharmacological profile. They are G-protein coupled, either positively linked to phospholipase C (class I) or negatively linked to adenylate cyclase (class II and III), and among other effects are known to induce phosphorylation of ionotropic glutamate receptors as well as modulate the excitability of neurons. Finally, they are heterogeneously distributed throughout the brain. 4. In hippocampal slice preparations, mGluRs have been shown to be involved in the induction of LTP in CA1 and dentate gyrus by some investigators, but others have failed to reproduce such experiments, leaving the question: what are the appropriate conditions for mGluR-mediated LTP? 5. In vivo, metabotropic receptor antagonists have been shown to block, and agonists to facilitate, induction and maintenance of LTP, mainly at perforant path/dentate granule cell synapses. As demonstrated in behavioral investigations, mGluRs apparently play an important part in hippocampus-dependent learning paradigms. As in LTP, antagonists block memory formation; in contrast to LTP, agonists also prevent memory formation. In memory recall metabotropic receptors seem to play no role. 6. Based on current information the authors develop models for a role of mGluRs in both LTP and memory formation. Activation of metabotropic receptors plays a particular modulatory role when high frequency stimulation is weak. Strong tetanization may bypass mGluRs by stimulating other systems leading to, at least phenomenologically, similar LTP, Behaviorally, mGluRs possibly set the signal to noise ratio of the hippocampal circuit.

Y-mazes are widely used for discrimination learning and spatial alternation tasks. We present here a computer-assisted Y-maze model for spatial alternation learning via footshock reinforcement. No intramaze cues are provided and handling between trials is no longer required. Pretraining application of scopolamine (1 mg kg-1) and D-AP5 (2-amino-5-phosphonopentanoate; 0.016 mg) clearly impairs acquisition and retention (tested 24 h after acquisition) of spatial alternation. These effects are not due to state-dependent changes caused by drug treatment. Similar results were reported by others in food-motivated spatial alternation tasks as well as spontaneous alternation paradigms. The data support our model as a useful tool for studying spatial alternation in the Y-maze.

Recently, it was demonstrated by the use of the competitive and selective antagonist ( R . S )- α -methyl-4-carboxyphenylglycine (MCPG) that metabotropic glutamate receptor (mGluR) activation is required to induce long-term potentiation (LTP) in the hippocampus. Accordingly, we investigated whether MCPG also inhibits spatial learning. Rats were trained on a spatial alternation task in a Y-maze with footshock reinforcement, and MCPG (0.0208 mg) was injected intracerebroventricularly prior to training and/or retention test. Animals injected pre-training are clearly impaired in retention, whereas preretention application was without effect. A state dependency could be excluded. Additionally, MCPG at the same concentration completely blocks a potentiation at perforant path/dentate gyrus synapses in vivo. These results strongly implicate a role of mGluRs in spatial learning and LTP.

During the postnatal period, male Wistar rats were treated with orotate, either from the 6th to 15th, 16th to 25th, or 26th to 35th day of life. Learning and memory were tested in adulthood. Rats that received orotate from the 6th to 15th day showed a better retention of a learned brightness discrimination (Y-maze) than controls. An active avoidance (pole jumping) was learned more quickly by the rats orotate-treated from the 6th to 15th day than by controls. The spontaneous locomotor activity of previously orotate-treated rats was the same as in controls. Body weight measurements revealed no differences between orotate rats and control rats. The results suggest that memory retention in adulthood can be improved by postnatal orotate treatment.

The effect of methylglucamine orotate (MGO) on learning and memory was investigated in 24-month-old rats using brightness discrimination in a Y-chamber and active avoidance in a shuttle box. In both learning procedures, an improvement of memory retention following 5-day MGO treatment (225 mg/kg per day) was observed. The retention of untreated old animals was significantly lower compared to 8-week-old rats. MGO treatment resulted in a significant improvement of retention in old rats, which nearly compensated for their memory deficit.

The effects of methylglucamine orotate (MGO) were studied on polygraphic sleep recordings in rats for 8 h per day between 8 a.m. and 4 p.m. MGO (225 mg/kg) was injected intraperitoneally immediately prior to the onset of recording. In the acute experiment, the effect of MGO was compared to pre- and post-drug control days. In the chronic experiment, a sequence of 5 control days, 10 days of MGO treatment, and a further 8 control days was tested. Both acute and chronic administration of MGO resulted in increased paradoxical sleep (PS) latency and a small, but significant, decrease in PS during the first 4 h after injection. This effect seems to be specific to PS, as no effects of MGO on waking or total sleep were found. With chronic administration, no PS rebound occurred within the 8-h recording time during the 8-day post-treatment control period. How the RNA precursor can decrease PS and whether this effect may play a role in the memory-improving action of the substance is discussed in terms of an interrelationship between macromolecular synthesis, sleep, and memory, respectively.

Intraperitoneal injection of a brain extract obtained from paradoxical sleep-(PS) deprived donor rats resulted in a small but significant increase of PS in normal recipient rats. Brain extract of non-deprived control rats was without effect. The results provide further evidence for the existence of a PS-inducing factor accumulating in the brain during PS deprivation.