Septal medial/diagonal band of Broca citalopram infusion reduces place learning efficiency and alters septohippocampal theta learning-related activity in rats.

Increases in power and frequency of hippocampal theta activity have been related to efficient place learning and memory acquisition in hippocampal-dependent tests. The complex medial septum-diagonal band of Broca (MS/DBB) is the pacemaker of hippocampal theta activity, influenced by the ascending synchronizing system, and modulated by serotonergic raphe medial afferents, acting on cholinergic and GABAergic septal neurons. The suppression of hippocampal theta expression and the modulation of hippocampal learning and memory are attributed to serotonin. To simultaneously test these hypotheses, a daily local serotonin increase was induced by citalopram (CIT) infusion (100 µM, 0.88 µl, 0.2 µl/m) 15 min before training in the Morris water maze. The theta activity was recorded in the MS/DBB, dentate gyrus (DG) and CA1 of one group infused with artificial cerebrospinal liquid (ACL) and the other with CIT on Days 1-6 of training. After a probe trial (Day 7) and one resting day, the treatments were reversed (Days 8-11). The CIT MS/DBB infusion in the first 6 training days reduced the efficiency of spatial learning in association with reduced power in the DG, reduced MS/DBB-DG coherence, increased DG-CA1 coherence, and a lack of a negative correlation between MS/DBB power and swam distances. No effect of the CIT occurred once the information was acquired under ACL training. These results support a role of serotonin, in acting on the MS/DBB in the fine tuning of hippocampal learning and memory efficiency through the modulation of learning-related theta activity power and septohipocampal synchronization.

Effects of Gestational Diabetes in Cognitive Behavior, Oxidative Stress and Metabolism on the Second-Generation Off-Spring of Rats.

Gestational diabetes (GD) has a negative impact on neurodevelopment, resulting in cognitive and neurological deficiencies. Oxidative stress (OS) has been reported in the brain of the first-generation offspring of GD rats. OS has been strongly associated with neurodegenerative diseases. In this work, we determined the effect of GD on the cognitive behavior, oxidative stress and metabolism of second-generation offspring. GD was induced with streptozotocin (STZ) in pregnant rats to obtain first-generation offspring (F1), next female F1 rats were mated with control males to obtain second-generation offspring (F2). Two and six-month-old F2 males and females were employed. Anxious-type behavior, spatial learning and spatial working memory were evaluated. In cerebral cortex and hippocampus, the oxidative stress and serum biochemical parameters were measured. Male F2 GD offspring presented the highest level of anxiety-type behavior, whilst females had the lowest level of anxiety-type behavior at juvenile age. In short-term memory, adult females presented deficiencies. The offspring F2 GD females presented modifications in oxidative stress biomarkers in the cerebral cortex as lipid-peroxidation, oxidized glutathione and catalase activity. We also observed metabolic disturbances, particularly in the lipid and insulin levels of male and female F2 GD offspring. Our results suggest a transgenerational effect of GD on metabolism, anxiety-like behavior, and spatial working memory.

Diabetic patients are deficient in intentional visuospatial learning and show different learning-related patterns of theta and gamma EEG activity.

Introduction: We hypothesized that diabetic patients without mild cognitive impairment would present deficiencies in visuospatial incidental/intentional memory processing and alterations in the underlying EEG alpha, theta and gamma patterns.Methods: Non-diabetic, diabetic-controlled, and diabetic-uncontrolled patients underwent a visuospatial incidental-intentional memory test under simultaneous recording of temporal, parietal, and frontal EEG. The test required patients to solve a maze, with eight objects irrelevant to the task, embedded in it, after an interference instruction, participants were asked to recall the positions of the objects (incidental test). Finally, the participants were explicitly told to study the object positions, and then were asked to recall the objects again (intentional test). Power from baseline, incidental learning, incidental memory, and intentional learning conditions was obtained in alpha, theta, and low-gamma bands. Comparisons were made across groups and conditions for each band, with age, sex, and years from the diagnosis as covariates (ANCOVA with blocking).Results: Diabetic patients showed spared incidental but deficient intentional visuospatial learning. Uncontrolled patients showed a more profound intentional learning deficit as they scored similar numbers of correct positions under incidental and intentional conditions; whereas, non-diabetic and diabetic-controlled patients increased their number after the intentional study. Non-diabetic participants showed increased power during intentional learning compared with the baseline condition in frontal theta, frontoparietal gamma (Fp2 and P4) and frontal alpha (F4) bands; whereas in diabetic patients the power increased in the theta band, in T5 (uncontrolled) and T5 and F7 (controlled).Conclusions: Diabetic patients without mild cognitive impairment show deficient intentional visuospatial learning which was worse in uncontrolled patients. Theta and gamma power increased in healthy participants during intentional learning principally in frontal areas. These EEG power changes were absent in diabetic patients. The reduced accuracy of diabetic patients in intentional visuospatial learning was associated with different EEG learning-related patterns.

Gestational Diabetes Triggers Oxidative Stress in Hippocampus and Cerebral Cortex and Cognitive Behavior Modifications in Rat Offspring: Age- and Sex-Dependent Effects.

Gestational diabetes (GD) has been linked with an increased risk of developing metabolic disorders and behavioral abnormalities in the offspring. Oxidative stress is strongly associated with neurodegeneration and cognitive disruption. In the offspring brains in a GD experimental rat model, increased oxidative stress in the prenatal and postnatal stages was reported. However, long-term alterations to offspring behavior and oxidative stress, caused by changes in the cerebral cortex and hippocampus, remain unclear. In this study, we evaluated the effect of GD on young and adult male and female rat offspring in metabolic parameters, cognitive behavior, and oxidative stress. GD was induced using streptozotocin in dams. Next, the offspring were evaluated at two and six months of age. Anxiety-like behavior was evaluated using the elevated plus maze and open field maze; spatial learning and short-term memory were evaluated using the Morris water maze and radial maze, respectively. We determined oxidative stress biomarkers (reactive oxygen species (ROS), lipid peroxidation and glutathione status) and antioxidant enzymes (superoxide dismutase and catalase) in the brain of offspring. We observed that male GD offspring showed a reduced level of anxiety at both ages as they spent less time in the closed arms of the elevated plus maze at adult age ((P = 0.019, d = 1.083 ( size effect)) and spent more time in the open area of an open field (P = 0.0412, d = 0.743) when young and adult age (P = 0.018, d = 0.65). Adult female GD offspring showed a reduced level of anxiety (P = 0.036; d = 0.966), and young female GD offspring showed a deficiency in spatial learning (P = 0.0291 vs. control, d = 3.207). Adult male GD offspring showed a deficiency in short-term memory (P = 0.017, d = 1.795). We found an increase in ROS and lipid peroxidation, a disruption in the glutathione status, and decreased activity of catalase and superoxide dismutase (P < 0.05 vs. control, d > 1.0), in the cerebral cortex and hippocampus of male and female GD offspring. GD altered metabolism; male offspring of both ages and adult females showed a high level of triglycerides and a lower level of high-density lipoprotein-cholesterol (P < 0.05 vs. control, d > 1.0). Young and adult female offspring displayed higher insulin levels (P < 0.05, d > 1.0). These results suggest that gestational diabetes modifies oxidative stress and cognitive behavior in an age- and sex-dependent manner.

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Neonatal Monosodium Glutamate Administration Disrupts Place Learning and Alters Hippocampal-Prefrontal Learning-Related Theta Activity in the Adult Rat.

Neonatal treatment with monosodium glutamate causes profound deficits in place learning and memory in adult rats evaluated in the Morris maze. Theta activity has been related to hippocampal learning, and increased high-frequency theta activity occurs through efficient place learning training in the Morris maze. We wondered whether the place learning deficits observed in adult rats that had been neonatally treated with monosodium glutamate (MSG), were related to altered theta patterns in the hippocampus and prelimbic cortex, which were recorded during place learning training in the Morris maze. The MSG-treated group had a profound deficit in place learning ability, with a marginal reduction in escape latencies during the final days of training. Learning-related changes were observed in the relative power distribution in control and MSG-treated groups in the hippocampal EEG, but not in the prelimbic cortex. Increased prefrontal and reduced hippocampal absolute power that appeared principally during the final days of training, and reduced coherence between regions throughout the training (4-12 Hz), were observed in the MSG-treated rats, thereby suggesting a misfunction of the circuits rather than a hyperexcitable general state. In conclusion, neonatal administration of MSG, which caused a profound deficit in place learning at the adult age, also altered the theta pattern both in the hippocampus and prelimbic cortex.

Aberrant connections between climbing fibres and Purkinje cells induce alterations in the timing of an instrumental response in the rat.

Cerebellar participation in timing and sensory-motor sequences has been supported by several experimental and clinical studies. A relevant role of the cerebellum in timing of conditioned responses in the range of milliseconds has been demonstrated, but less is known regarding the role of the cerebellum in supra-second timing of operant responses. A dissociated role of the cerebellum and striatum in timing in the millisecond and second range had been reported, respectively. The climbing fibre-Purkinje cell synapse is crucial in timing models; thus, the aberrant connection between these cellular elements is a suitable model for evaluating the contribution of the cerebellum in timing in the supra-second range. The aberrant connection between climbing fibres and Purkinje cells was induced by administration of the antagonist of NMDA receptors MK-801 to Sprague-Dawley rats at postnatal days 7-14. The timing of an operant response with two fixed intervals (5 and 8 s) and egocentric sequential learning was evaluated in 60-day-old adult rats. The aberrant connections caused a reduced accuracy in the timing of the instrumental response that was more evident in the 8-s interval and a reduced number of successive correct responses (responses emitted in the correct second without any other response between them) in the 8-s interval. In addition, an inability to incorporate new information in a sequence previously learned in egocentric-based sequence learning was apparent in rats with aberrant CF-PC synapses. These results support a relevant role for the cerebellum in the fine-tuning of the timing of operant responses in the supra-second range.

Differences in EEG power in young and mature healthy adults during an incidental/spatial learning task are related to age and execution efficiency.

The differential characteristics of absolute power in the EEG theta (4-8 Hz) and gamma (30-45 Hz) frequency bands have been analysed in young (18-25 years old, n = 14) and mature adults (45-65 years old, n = 12) during the incidental or intentional behavioural conditions of learning and recalling in a visuospatial task. A printed drawing of a maze including eight figures of common objects in specific placements, solved by connecting its entrance and exit points, allowed the subject's performance efficiency to be measured based on the number, position accuracy and/or identity of incidentally or intentionally learned and remembered objects. Meanwhile, EEG recordings from frontal, parietal and temporal derivations were obtained to determine the power values of the theta (4-8 Hz) and gamma (30-45 Hz) bands for each behavioural condition and derivation. Relative to the young adults, the mature adults generally showed lower absolute theta power values, mainly due to their low theta powers under the basal and incidental learning conditions, and higher absolute gamma power values in the frontal and temporal regions. Furthermore, higher theta band power in the frontal regions was related to higher performance efficiency in both incidental and intentional learning, regardless of the subjects' age. A significant negative correlation between the parameters of individual incidental or intentional learning performance and age was also found. Indeed, a differential accuracy of remembered information seems to be associated with age and incidental or intentional learning/memory testing conditions. These data support an increasing vulnerability of visuospatial learning abilities at mature ages and as ageing progresses.

Septal serotonin depletion in rats facilitates working memory in the radial arm maze and increases hippocampal high-frequency theta activity.

Hippocampal theta activity, which is strongly modulated by the septal medial/Broca׳s diagonal band neurons, has been linked to information processing of the hippocampus. Serotonin from the medial raphe nuclei desynchronises hippocampal theta activity, whereas inactivation or a lesion of this nucleus induces continuous and persistent theta activity in the hippocampus. Hippocampal serotonin depletion produces an increased expression of high-frequency theta activity concurrent with the facilitation of place learning in the Morris maze. The medial septum-diagonal band of Broca complex (MS/DBB) has been proposed as a key structure in the serotonin modulation of theta activity. We addressed whether serotonin depletion of the MS/DBB induces changes in the characteristics of hippocampal theta activity and whether the depletion is associated with learning in a working memory spatial task in the radial arm maze. Sprague Dawley rats were depleted of 5HT with the infusion of 5,7-dihydroxytriptamine (5,7-DHT) in MS/DBB and were subsequently trained in the standard test (win-shift) in the radial arm, while the CA1 EEG activity was simultaneously recorded through telemetry. The MS/DBB serotonin depletion induced a low level of expression of low-frequency (4.5-6.5Hz) and a higher expression of high-frequency (6.5-9.5Hz) theta activity concomitant to a minor number of errors committed by rats on the working memory test. Thus, the depletion of serotonin in the MS/DBB caused a facilitator effect on working memory and a predominance of high-frequency theta activity.

Serotonergic modulation of hippocampal theta activity in relation to hippocampal information processing.

Hippocampal theta activity is the result of the concerted activity of a group of nuclei located in the brain stem and the caudal diencephalic area, which are together referred to as the synchronizing ascending system. Serotonin is recognized as the only neurotransmitter able to desynchronize the hippocampal electroencephalographic. A theory has been developed in which serotonin, acting on medial septal neurons, modulates cholinergic/GABAergic inputs to the hippocampus and, thus, the cognitive processing mediated by this area. However, few studies have addressed the relationship between serotonin modulation of theta activity and cognition. In this review, we present a summary and analysis of the data relating serotonin and its theta activity modulation with cognition, and we also discuss the few works relating serotonin, theta activity and cognition as well as the theories regarding the serotonin regulation of memory processes organized by the hippocampus. We propose that serotonin depletion induces impairment of the relays coding the frequency of hippocampal theta activity, whereas depletion of the relays in which frequency is not coded induces improvements in spatial learning that are related to increased expression of high-frequency theta activity.

Serotonin depletion of supramammillary/posterior hypothalamus nuclei produces place learning deficiencies and alters the concomitant hippocampal theta activity in rats.

Hippocampal theta activity is important for the acquisition of spatial information and is strongly influenced and regulated by extra-hippocampal inputs from the synchronising ascending system (SAS), which includes the supramammillary nucleus (SUMn) and the posterior hypothalamic nucleus (PHn). Together these nuclei play an important role in controlling the frequency encoding of theta activity and are innervated by serotonin synapses, which also regulate theta activity and learning abilities. The participation of the SUMn in place learning and modulation of hippocampal theta activity were recently shown; thus, we questioned whether serotonin acting on SUMn/PHn could modulate place learning ability and concurrent hippocampal theta activity. The serotonergic terminals of the SUMn/PHn in rats were lesioned through 5,7-dihydroxytryptamine (5,7-DHT) infusion, and hippocampal theta activity during the Morris water maze test was recorded. Rats in the vehicle group learned the task efficiently and showed learning-related theta changes in the CA1 and dentate gyrus regions throughout the training. The 5-HT-depleted rats were deficient in the Morris water maze task and showed theta activity in the CA1 and dentate gyrus that were unrelated to the processing of learning. We conclude that serotonin can regulate the hippocampal theta activity acting on the SUMn/PHn relay of the SAS and that the influence of 5-HT in these nuclei is required for the learning-related changes in hippocampal theta activity that underlie the successful resolution of the Morris water maze task.

Differential learning-related changes in theta activity during place learning in young and old rats.

The participation key role of the hippocampus in place learning ability as well as the decline of cognitive functions associated with aging, have been established in experimental and clinical studies. On the other hand, hippocampal theta activity has been proposed as a part of the cerebral phenomena underlying hippocampal-dependent learning processes. In the present study, the relative power of low, high, and maximal frequency components of hippocampal CA1 theta activity during a 6-day training period (four daily trials; basal, searching, and platform stages) and the probe trial of a place learning paradigm (Morris water maze) were analyzed in young and aged rats. An increase in high frequency, and a decrease in low frequency relative power of theta activity during the searching stage, which were correlated with shorter swimming path lengths and predominant hippocampal-dependent allocentric strategies, were observed in young rats as became trained in place learning and memory tasks, in the Morris water maze; while, under these conditions, no changes in theta activity and predominant non hippocampal-dependent egocentric strategies occurred in the old rats. Besides, an overall (theta activity recorded during the three behavioral stages) increase of low frequency and an overall decrease of high frequency theta bands in the old group as compared to the young group were observed. These electrophysiological data suggest that old rats process information relevant for cognitive functions in a different manner, possibly leading to the use of different learning strategies, than young rats.

Hippocampal serotonin depletion facilitates place learning concurrent with an increase in CA1 high frequency theta activity expression in the rat.

Acetylcholine- and serotonin-dependent theta activities have been long proposed to exist. However, several studies have shown that serotonin tends to desynchronise hippocampal EEG activity. Theta activity has been related to the processing of hippocampal place learning. Since the serotonergic system can influence hippocampal theta activity, it could function as a modulator of spatial learning. For these reasons, we investigated the possible role of hippocampal serotonin in the regulation of theta activity during the acquisition of map-based spatial information. Following 5-HT hippocampal depletion through 5,7-dihydroxytriptamine-induced lesions to the fimbria, fornix and cingulate bundle of adult rats, CA1 hippocampal theta activity was recorded during place learning training. Only rats with reduction higher than 90% from controls, verified post-mortem by HPLC were studied. A facilitation of place learning after hippocampal serotonin depletion occurred, and was associated with earlier expression of dominant high frequency theta activity (6.5-9.5Hz). Therefore, theta activity was related to the accuracy of behavioural performance through 5-HT modulation in a place learning test.

Serotonin/dopamine interaction in learning.

Dopamine (DA)-serotonin interactions dealing with learning and memory functions have been apparent from experimental approaches over the past decade. However, since the former evidence showing that these cerebral neurotransmitter systems are involved in the regulation of the same cognitive processes, few experimental studies have been done to further clarify the nature of DA-serotonin interactions for cognitive processes sharing common brain structures. Nevertheless, a regulatory role of 5-HT/DA interactions in cognition and the prefrontal cortex (PFC) and the striatum as a neuroanatomical substrate for these DA/5-HT interactions, are now recognized. Experimental evidence indicates that pharmacological disruption of serotonin neurotransmission results in a facilitative effect on the processing of mnemonic information by cerebral regions under strong, functional DA modulation, such as the striatum and the PFC; on the other hand, increased serotonin neurotransmission appears to have a detrimental effect on cognitive functions integrated in these structures. These effects seem to occur through the interaction of different pre- and postsynaptic DA and serotonin receptor subtypes acting as opposite systems underlying cognitive abilities. Some studies, focused on DA-serotonin interactions underlying the pathophysiology of neurological and psychiatric diseases, which evolve with cognitive dysfunctions in human beings, have shown that drugs that are able to modify DA or serotonin neurotransmission may exert beneficial effects on cognitive functions, even though improvement of motor, mood and behavioural disturbances are the main objectives of pharmacological treatment of these diseases. The complete significance of DA-serotonin interactions in cognitive functions could be addressed by future experimental and clinical studies.