Intracranial self-stimulation reverses impaired spatial learning and regulates serum microRNA levels in a streptozotocin-induced rat model of Alzheimer disease.

BACKGROUND: The assessment of deep brain stimulation (DBS) as a therapeutic alternative for treating Alzheimer disease (AD) is ongoing. We aimed to determine the effects of intracranial self-stimulation at the medial forebrain bundle (MFB-ICSS) on spatial memory, neurodegeneration, and serum expression of microRNAs (miRNAs) in a rat model of sporadic AD created by injection of streptozotocin. We hypothesized that MFB-ICSS would reverse the behavioural effects of streptozotocin and modulate hippocampal neuronal density and serum levels of the miRNAs. METHODS: We performed Morris water maze and light-dark transition tests. Levels of various proteins, specifically amyloid-ß precurser protein (APP), phosphorylated tau protein (pTAU), and sirtuin 1 (SIRT1), and neurodegeneration were analyzed by Western blot and Nissl staining, respectively. Serum miRNA expression was measured by reverse transcription polymerase chain reaction. RESULTS: Male rats that received streptozotocin had increased hippocampal levels of pTAU S202/T205, APP, and SIRT1 proteins; increased neurodegeneration in the CA1, dentate gyrus (DG), and dorsal tenia tecta; and worse performance in the Morris water maze task. No differences were observed in miRNAs, except for miR-181c and miR-let-7b. After MFB-ICSS, neuronal density in the CA1 and DG regions and levels of miR-181c in streptozotocin-treated and control rats were similar. Rats that received streptozotocin and underwent MFB-ICSS also showed lower levels of miR-let-7b and better spatial learning than rats that received streptozotocin without MFB-ICSS. LIMITATIONS: The reversal by MFB-ICSS of deficits induced by streptozotocin was fairly modest. CONCLUSION: Spatial memory performance, hippocampal neurodegeneration, and serum levels of miR-let-7b and miR-181c were affected by MFB-ICSS under AD-like conditions. Our results validate the MFB as a potential target for DBS and lend support to the use of specific miRNAs as promising biomarkers of the effectiveness of DBS in combatting AD-associated cognitive deficits.

Orexin-1 receptor blockade differentially affects spatial and visual discrimination memory facilitation by intracranial self-stimulation.

Intracranial self-stimulation (ICSS) of the medial forebrain bundle is an effective treatment to facilitate memory. Performance in both explicit and implicit memory tasks has been improved by ICSS, and this treatment has even been capable of recovering loss of memory function due to lesions or old age. Several neurochemical systems have been studied in regard to their role in ICSS effects on memory, however the possible involvement of the orexinergic system in this facilitation has yet to be explored. The present study aims to examine the relationship between the OX1R and the facilitative effects of ICSS on two different types of memory tasks, both carried out in the Morris Water Maze: spatial and visual discrimination. Results show that the OX1R blockade, by intraventricular administration of SB-334867, partially negates the facilitating effect of ICSS on spatial memory, whereas it hinders ICSS facilitation of the discrimination task. However, ICSS treatment was capable of compensating for the severe detrimental effects of OX1R blockade on both memory paradigms. These results suggest different levels of involvement of the orexinergic system in the facilitation of memory by ICSS, depending on the memory task.

Arc protein expression after unilateral intracranial self-stimulation of the medial forebrain bundle is upregulated in specific nuclei of memory-related areas.

BACKGROUND: Intracranial Self-Stimulation (ICSS) of the medial forebrain bundle (MFB) is a deep brain stimulation procedure, which has a powerful enhancement effect on explicit and implicit memory. However, the downstream synaptic plasticity events of MFB-ICSS in memory related areas have not been described thoroughly. This study complements previous work studying the effect of MFB-ICSS on the expression of the activity-regulated cytoskeleton-associated (Arc) protein, which has been widely established as a synaptic plasticity marker. We provide new integrated measurements from memory related regions and take possible regional hemispheric differences into consideration. RESULTS: Arc protein expression levels were analyzed 4.5 h after MFB-ICSS by immunohistochemistry in the hippocampus, habenula, and memory related amygdalar and thalamic nuclei, in both the ipsilateral and contralateral hemispheres to the stimulating electrode location. MFB-ICSS was performed using the same paradigm which has previously been shown to facilitate memory. Our findings illustrate that MFB-ICSS upregulates the expression of Arc protein in the oriens and radiatum layers of ipsilateral CA1 and contralateral CA3 hippocampal regions; the hilus bilaterally, the lateral amygdala and dorsolateral thalamic areas as well as the central medial thalamic nucleus. In contrast, the central amygdala, mediodorsal and paraventricular thalamic nuclei, and the habenular complex did not show changes in Arc expression after MFB-ICSS. CONCLUSIONS: Our results expand our knowledge of which specific memory related areas MFB-ICSS activates and, motivates the definition of three functionally separate groups according to their Arc-related synaptic plasticity response: (1) the hippocampus and dorsolateral thalamic area, (2) the central medial thalamic area and (3) the lateral amygdala.

Increase in c-Fos and Arc protein in retrosplenial cortex after memory-improving lateral hypothalamic electrical stimulation treatment.

Post-training Intracranial self-stimulation (ICSS) of the lateral hypothalamus (LH), a kind of rewarding deep-brain stimulation, potentiates learning and memory and increases c-Fos protein expression in specific memory-related brain regions. In a previous study, Aldavert-Vera et al. (2013) reported that post-acquisition LH-ICSS improved 48 h retention of a delay two-way active avoidance conditioning (TWAA) and induced c-Fos expression increase in CA3 at 90 min after administration. Nevertheless, this c-Fos induction was only observed after the acquisition session and not after the retention test at 48 h, when the ICSS improving effect was observed on memory. This current study aims to examine the hypothesis that post-training ICSS treatment may stimulate c-Fos expression at the time of the TWAA retention test in retrosplenial cortex (RSC), a hippocampus-related brain region more closely related with long-lasting memory storage. Effects of ICSS on Arc protein, a marker of memory-associated synaptic plasticity, were also measured by immunohistochemistry in granular and agranular RSC. The most innovative results are that the ICSS treatment potentiates the c-Fos induction across TWAA conditions (no conditioning, acquisition and retention), specifically in layer V of the granular RSC, along with increases of Arc protein levels in the granular but not in agranular areas of RSC ipsilaterally few hours after ICSS. This leads us to suggest that plasticity-related protein activation in the granular RSC could be involved in the positive modulatory effects of ICSS on TWAA memory consolidation, opening a new approach for future research in ICSS memory facilitation.

Intracranial Self-stimulation of the Medial Forebrain Bundle Ameliorates Memory Disturbances and Pathological Hallmarks in an Alzheimer's Disease Model by Intracerebral Administration of Amyloid-ß in Rats.

No curative or fully effective treatments are currently available for Alzheimer's disease (AD), the most common form of dementia. Electrical stimulation of deep brain areas has been proposed as a novel neuromodulatory therapeutic approach. Previous research from our lab demonstrates that intracranial self-stimulation (ICSS) targeting medial forebrain bundle (MFB) facilitates explicit and implicit learning and memory in rats with age or lesion-related memory impairment. At a molecular level, MFB-ICSS modulates the expression of plasticity and neuroprotection-related genes in memory-related brain areas. On this basis, we suggest that MFB could be a promising stimulation target for AD treatment. In this study, we aimed to assess the effects of MFB-ICSS on both explicit memory as well as the levels of neuropathological markers ptau and drebrin (DBN) in memory-related areas, in an AD rat model obtained by Aß icv-injection. A total of 36 male rats were trained in the Morris water maze on days 26-30 after Aß injection and tested on day 33. Results demonstrate that this Aß model displayed spatial memory impairment in the retention test, accompanied by changes in the levels of DBN and ptau in lateral entorhinal cortex and hippocampus, resembling pathological alterations in early AD. Administration of MFB-ICSS treatment consisting of 5 post-training sessions to AD rats managed to reverse the memory deficits as well as the alteration in ptau and DBN levels. Thus, this paper reports both cognitive and molecular effects of a post-training reinforcing deep brain stimulation procedure in a sporadic AD model for the first time.

Intracranial Self-Stimulation and Memory in Rats: A Sistematic Review.

BACKGROUND: Intracranial self-stimulation (ICSS) is a technique by which rats press a lever to stimulate their brains through an electrode chronically implanted in brain reward areas. Currently only two laboratories in the world, one in India and one in Spain, are intensively studying the effect of this kind of deep brain stimulation on learning and memory. This paper will present the main findings. METHODS: Different groups of young and old healthy and brain-damaged rats with electrodes implanted in the medial forebrain bundle received a treatment of ICSS after being trained in several paradigms of implicit and explicit learning. Memory was tested over short and long-term periods. Structural and molecular post-mortem analyses of their brains were examined in relation to memory results. RESULTS: ICSS enhances implicit and explicit memory, especially in animals showing poor performance in the learning tasks, such as brain-damaged subjects. At the structural and molecular level, ICSS enhances size and dendritic arborization and promotes neurogenesis in specific hippocampal areas. ICSS also regulates the expression of genes related to learning and memory. CONCLUSIONS: Through activating reward and neural plasticity mechanisms, ICSS in the medial forebrain bundle is a promising technique for memory-enhancing treatments.

Protocol to assess rewarding brain stimulation as a learning and memory modulating treatment: Comparison between self-administration and experimenter-administration.

Intracranial electrical self-stimulation (ICSS) is a useful procedure in animal research. This form of administration ensures that areas of the brain reward system (BRS) are being functionally activated, since the animals must perform an operant response to self-administer an electrical stimulus. Rewarding post-training ICSS of the medial forebrain bundle (MFB), an important system of the BRS, has been shown to consistently improve rats' acquisition and retention in several learning tasks. In the clinical setting, deep brain stimulation (DBS) of different targets is currently being used to palliate the memory impairment that occurs in some neurodegenerative diseases. However, the stimulation of the MFB has only been used to treat emotional alterations, not memory disorders. Since DBS stimulation treatments in humans are exclusively administered by external sources, studies comparing the efficacy of that form of application to a self-administered stimulation are key to the translationality of ICSS. This protocol compares self-administered (ICSS) and experimenter-administered (EAS) stimulation of the MFB on the spatial Morris Water Maze task (MWM). c-Fos immunohistochemistry procedure was carried out to evaluate neural activation after retention. Results show that the stimulation of the MFB improves the MWM task regardless of the form of administration, although some differences in c-Fos expression were found. Present results suggest that MFB-ICSS is a valid animal model to study the effects of MFB electrical stimulation on memory, which could guide clinical applications of DBS. The present protocol is a useful guide for establishing ICSS behavior in rats, which could be used as a learning and memory-modulating treatment.

Intracranial self-stimulation recovers learning and memory capacity in basolateral amygdala-damaged rats.

We studied the capacity of post-training intracranial self-stimulation (SS) to reverse or ameliorate learning and memory impairments caused by amygdala damage in rats. A first experiment showed that lesions of the basolateral amygdala (BLA) slow down acquisition of two-way active avoidance conditioning (2wAA). In a second experiment we observed that a post-training SS treatment administered immediately after each 2wAA conditioning session is able to completely reverse the disruptive effects of the BLA lesions, and the facilitative effect lasts for 10days. A third experiment allowed us to differentiate the strong recuperative effects of the SS treatment from the slight effect caused by overtraining the same conditioning response. We concluded that SS is able to counteract the behavioral deficit induced by BLA damage, probably by activating alternative undamaged brain structures related to learning and memory, such as the hippocampus.

[Analysis of the efficacy and factors influencing the response of secondary hyperparathyroidism patients on hemodialysis to cinacalcet]. / Análisis de la eficacia y de los factores que influyen en la respuesta del hiperparatiroidismo secundario de pacientes en hemodiálisis a cinacalcet.

BACKGROUND: Treatment of secondary hyperparathyroidism with cinacalcet improves control of PTH, phosphorus, calcium and Ca x P product, enabling to achieve targets recommended by K/DOQI guidelines for PTHi in only 30-50% of patients, in studies with a very selected population. The aim of this study was to analyze its effectiveness in real clinical practice, comparing results with targets recommended by K/DOQI and KDIGO guidelines and to investigate factors having influence on PTH responsiveness to cinacalcet. METHODS: We collected data of evolution of 74 patients on hemodialysis with secondary hyperparathyroidism who were treated with cinacalcet for at least 6 months. RESULTS: According K/DOQI targets we observed a reduction of proportion of patients with PTHi > 300 pg/ml to 50%, a decrease of hyperphosphoremia from 38.4% to 23.3% and proportion of patients with Ca x P product > 55 mg2/dl2 from 37.8% to 15.1%. By contrast, presence of hypocalcemia increases from 2.7% to 12.3%. Comparing with KDIGO targets, proportion of patients with PTHi > 600 pg/ml decreased from 41.1% to 16.4% and with hyperphosphoremia from 68.5% to 52.1%. However, when considering patients with baseline PTHi > 600 pg/ml prevalence of P > 4.5 mg/dl decreased from 83.3% to 55.2%. We observed significant changes of phosphate binders after cinacalcet treatment with an increase in calcium carbonate doses (pre 0.61 +/- 1.53 g of calcium/day vs post-cinacalcet 0.95 +/- 1.98 g of calcium/day; p = 0.03) that was prescribed to prevent hypocalcemia and not as phosphate binder. Responsiveness were lower in patients who were taking higher doses of sevelamer at baseline, showing at the end of the study higher PTHi (no-sevelamer: 312 +/- 245 pg/ml; sevelamer < 6.4 g/day: 510 +/- 490 pg/ml; sevelamer > 6.4 g/day: 526 +/- 393 pg/ml; p = 0.04) and phosphorus (no-sevelamer: 4.5 +/- 1.2 mg/dl; sevelamer < 6.4 g/day: 4.2 +/- 1.5 mg/dl; sevelamer > 6.4 g/day: 5.7 +/- 0.9 mg/dl; p=0.01) serum levels. Use of paricalcitol did not show any influence on PTH response. Patients achieving targets for PTH at the end of the study showed a good response early, with a significant decrease of PTHi levels at three months (159 +/- 84 vs 630 +/- 377 pg/ml; p < 0.001) with significantly lower doses of cinacalcet (33.8 +/- 22.5 vs 51.1 +/- 25.1 mg/day; p = 0.003). Using multivariate analysis we found that percent of PTHi reduction was related with baseline PTHi levels and taking sevelamer as phosphate binder at baseline. CONCLUSION: Use of cinacalcet improves grade of control of secondary hyperparathyroidism in non-selected patients in hemodialysis, showing poor response in population with higher PTHi levels and who takes higher doses of sevelamer at baseline. By contrast, a reduction of PTHi levels at 3 months of treatment with relatively lower doses is a pronostic marker of good response to cinacalcet treatment.

Intracranial Self-Stimulation Modulates Levels of SIRT1 Protein and Neural Plasticity-Related microRNAs.

Deep brain stimulation (DBS) of reward system brain areas, such as the medial forebrain bundle (MFB), by means of intracranial self-stimulation (ICSS), facilitates learning and memory in rodents. MFB-ICSS has been found capable of modifying different plasticity-related proteins, but its underlying molecular mechanisms require further elucidation. MicroRNAs (miRNAs) and the longevity-associated SIRT1 protein have emerged as important regulatory molecules implicated in neural plasticity. Thus, we aimed to analyze the effects of MFB-ICSS on miRNAs expression and SIRT1 protein levels in hippocampal subfields and serum. We used OpenArray to select miRNA candidates differentially expressed in the dentate gyrus (DG) of ICSS-treated (3 sessions, 45' session/day) and sham rats. We further analyzed the expression of these miRNAs, together with candidates selected after bibliographic screening (miR-132-3p, miR-134-5p, miR-146a-5p, miR-181c-5p) in DG, CA1, and CA3, as well as in serum, by qRT-PCR. We also assessed tissue and serum SIRT1 protein levels by Western Blot and ELISA, respectively. Expression of miR-132-3p, miR-181c-5p, miR-495-3p, and SIRT1 protein was upregulated in DG of ICSS rats (P < 0.05). None of the analyzed molecules was regulated in CA3, while miR-132-3p was also increased in CA1 (P = 0.011) and serum (P = 0.048). This work shows for the first time that a DBS procedure, specifically MFB-ICSS, modulates the levels of plasticity-related miRNAs and SIRT1 in specific hippocampal subfields. The mechanistic role of these molecules could be key to the improvement of memory by MFB-ICSS. Moreover, regarding the proposed clinical applicability of DBS, serum miR-132 is suggested as a potential treatment biomarker.

Rewarding deep brain stimulation at the medial forebrain bundle favours avoidance conditioned response in a remote memory test, hinders extinction and increases neurogenesis.

Intracranial Self-Stimulation (ICSS) at the medial forebrain bundle consistently facilitates learning and memory in rats when administered post-training or when administered non-concurrent to training, but its scope regarding remote memory has not yet been studied. The present work aims to test whether the combination of these two forms of ICSS administration can cause a greater persistence of the facilitating effect on remote retention and affect neurogenesis in the dentate gyrus (DG) of the hippocampus. Rats were trained in active avoidance conditioning and tested in two retention sessions (10 and 90 days) and later extinction. Subjects received an ICSS session after each of the five avoidance acquisition sessions (post-training treatment) and half of them also received ten additional ICSS sessions during the rest period between retention tests (non-concurrent treatment). All the stimulated groups showed a higher performance in acquisition and retention sessions, but only the rats receiving both ICSS treatments showed greater resistance to extinction. Remarkably, at seven months, rats receiving the non-concurrent ICSS treatment had a greater number of DCX-positive cells in the DG as well as a higher amount of new-born cells within the granular layer compared to rats that did not receive this additional ICSS treatment. Our present findings significantly extend the temporal window of the facilitating effect of ICSS on active avoidance and demonstrate a neurogenic effect of rewarding medial forebrain bundle stimulation.

Altered expression of dopaminergic cell fate regulating genes prior to manifestation of symptoms in a transgenic rat model of Huntington's disease.

Hyperactivity of the dopaminergic pathway is thought to contribute to clinical symptoms in the early stages of Huntington's disease (HD). It is suggested to be result of a reduced dopaminergic inhibition by degeneration of medium spiny neurons in the striatum. Previously, we have shown that the number of dopaminergic cells is increased in the dorsal raphe nucleus (DRN) of HD patients and transgenic HD (tgHD) rats during the manifestation phase of the disease; as well as in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) of tgHD rats. To address whether these changes are secondary to neurodegeneration or take place in the pre-manifest phase of the disease, we examined the expression of genes controlling neuronal cell fate and genes that define dopaminergic cell phenotype. In the SNc-VTA of tgHD rats, Msx1 was upregulated, which correlated with an altered expression of transcription factors Zbtb16 and Tcf12. Zbtb16 was upregulated in the DRN and it was the only gene that showed a correlated expression in the tgHD rats between SNc-VTA and DRN. Zbtb16 may be a candidate for regionally tuning its cell populations, resulting in the increase in dopaminergic cells observed in our previous studies. Here, we demonstrated an altered expression of genes related to dopaminergic cell fate regulation in the brainstem of 6 months-old tgHD rats. This suggests that changes in dopaminergic system in HD precede the manifestation of clinical symptoms, contradicting the theory that hyperdopaminergic status in HD is a consequence of neurodegeneration in the striatum.

Intracranial self-stimulation improves memory consolidation in rats with little training.

Post-training intracranial electrical self-stimulation can improve learning and memory consolidation in rats. However, the molecular mechanisms involved are not known yet. Since previous paradigms of this kind of facilitation are relatively unsuitable to try a molecular approach, here we develop a single and short model of learning and memory facilitation by post-training self-stimulation that could make easier the research of its neural and molecular basis. Thus, three consecutive experiments were carried out to ascertain whether post-training self-stimulation is able to facilitate memory when learning consists of only a brief (5 trials) two-way active avoidance conditioning session. The results of Experiment 1 showed that it is actually possible, and that 48 h after the acquisition session is a very good time to observe the memory improvement. As a way to probe the retroactive effect of self-stimulation, in Experiment 2 we observed that the same self-stimulation treatment given to the subjects not post-training but 48 h before a single two-way active avoidance session does not improve the acquisition of conditioning. In Experiment 3, we showed that the SS facilitative effect observed 48 h after the acquisition session in Experiment 1 was still maintained one week later. We concluded that post-training intracranial self-stimulation can consistently improve memory consolidation even when little acquisition training is given to the animals in a single training session.

Spaced sessions of avoidance extinction reduce spontaneous recovery and promote infralimbic cortex activation.

Extinction-based therapies (EBT) are the psychological treatments of choice for certain anxiety disorders, such as post-traumatic stress disorder. However, some patients relapse and suffer spontaneous recovery (SR) of anxiety symptoms and persistence of avoidance behaviour, which underlines the need for improving EBT. In rats, recent evidence has highlighted the relevance of the temporal distribution of extinction sessions in reducing SR of auditory fear conditioning, although it has seldom been studied in procedures involving proactive avoidance responses, such as two-way active avoidance conditioning (TWAA). We examined whether the temporal distribution of two extinction sessions separated by 24h or 7days (contiguous versus spaced extinction paradigms, respectively), influences SR after 28days of a TWAA task. c-Fos expression, as a marker of neuronal activation, was also measured by immunohistochemistry 90min after the SR test in the amygdala and the medial prefrontal cortex. The temporal distribution of extinction sessions did not affect the degree of extinction learning. However, only the rats that underwent the 7-day spaced extinction paradigm maintained the level of extinction in the long term, showing no SR in TWAA. This behavioural finding was consistent with a greater number of c-Fos-labelled neurons in the infralimbic cortex in the 7-day group, and in the Lateral and Central nuclei of the amygdala in the 24-hour group. These findings show that a time-spaced extinction paradigm reduces the spontaneous recovery of active avoidance behaviour, and that this behavioural advantage appears to be related to the activation of the infralimbic cortex.

Increased training compensates for OX1R blockage-impairment of spatial memory and c-Fos expression in different cortical and subcortical areas.

It has been suggested that the orexin system modulates learning and memory-related processes. However, the possible influence that training could have on the effect of the blockade of orexin-A selective receptor (OX1R) on a spatial memory task has not been explored. Therefore, the present study attempts to compare the effects of OX1R antagonist SB-334867 infusion on spatial memory in two different conditions in the Morris Water Maze (MWM). This experiment evaluated the animals' performance in weak training (2 trials per session) vs strong training (6 trials per session) protocols in a spatial version of the MWM. We found that in the 2-trial condition the post-training SB-334867 infusion had a negative effect on consolidation as well as on the retention and reversal learning of the task 72 h later. This effect was not apparent in the 6-trial condition. In addition, while the strong training groups showed a general increase in c-Fos expression in several brain areas of the hippocampal-thalamic-cortical circuit, SB-334867 administration had the opposite effect in areas that have been previously reported to have a high density of OX1R. Specifically, the SB-infused group in the 2-trial condition showed a decrease in c-Fos immunoreactivity in the dentate gyrus, granular retrosplenial and prelimbic cortices, and centrolateral thalamic nucleus. This was not observed for subjects in the 6-trial condition. The activation of these areas could constitute a neuroanatomical substrate involved in the compensatory mechanisms of training upon SB-334867 impairing effects on a MWM spatial task.

Intracranial self-stimulation after memory reactivation: immediate and late effects.

To assess whether intracranial self-stimulation (SS) given after memory reactivation could improve memory retrieval, we tested the immediate (Experiment 1) and late (24 h; Experiment 2) effects of an SS treatment on the retrieval of a two-way active avoidance conditioning in Wistar rats. Memory was reactivated 24 h after training and the reminder (Rm) used consisted of a 3 s exposure to the conditioned stimulus (a tone) in the same context as in the original learning. SS treatment (2500 trains at 100% of each rat's optimal intensity) was administered immediately afterwards. No significant differences between SS-treated and control groups were observed when the retrieval was tested immediately after the SS treatment with or without memory reactivation. However, retrieval was improved when tested 24 h after SS treatment alone or after the reminder exposure alone. The greatest improvement in avoidance was observed when both treatments were given together, that is, when the SS treatment was administered immediately after memory reactivation. Moreover, there were no significant statistical interactions between the effect of SS treatment and the ones of memory reactivation in any of both experiments. The present results show that the effect of an immediate SS treatment can be added to the ones of memory reactivation causing a strong long-term facilitation of memory retrieval.

Intracranial Self-Stimulation and Memory in Rats: A Sistematic Review / Autoestimulación Eléctrica Intracraneal y Memoria en Ratas: una Revisión Sistemática

Background: Intracranial self-stimulation (ICSS) is a technique by which rats press a lever to stimulate their brains through an electrode chronically implanted in brain reward areas. Currently only two laboratories in the world, one in India and one in Spain, are intensively studying the effect of this kind of deep brain stimulation on learning and memory. This paper will present the main findings. Methods: Different groups of young and old healthy and brain-damaged rats with electrodes implanted in the medial forebrain bundle received a treatment of ICSS after being trained in several paradigms of implicit and explicit learning. Memory was tested over short and long-term periods. Structural and molecular post-mortem analyses of their brains were examined in relation to memory results. Results: ICSS enhances implicit and explicit memory, especially in animals showing poor performance in the learning tasks, such as brain-damaged subjects. At the structural and molecular level, ICSS enhances size and dendritic arborization and promotes neurogenesis in specific hippocampal areas. ICSS also regulates the expression of genes related to learning and memory. Conclusions: Through activating reward and neural plasticity mechanisms, ICSS in the medial forebrain bundle is a promising technique for memory-enhancing treatments.(AU)

Antecedentes: La autoestimulación eléctrica intracraneal (AEIC) es un tipo de estimulación cerebral profunda autoadministrada a través de un electrodo implantado de forma crónica en áreas cerebrales de la recompensa. Actualmente, dos laboratorios en el mundo, uno en India y otro en España, están estudiando intensivamente el efecto de este tipo de estimulación cerebral reforzante sobre el aprendizaje y la memoria. Aquí se presentan los principales hallazgos. Métodos: Diferentes grupos de ratas sanas y con daño cerebral, jóvenes y viejas, con electrodos implantados en el haz prosencefálico medial recibieron un tratamiento de AEIC después de ser entrenados en diferentes paradigmas de aprendizaje. La memoria se evaluó a corto y largo plazo. Resultados: La AEIC mejora la memoria implícita y explícita, especialmente en animales con un bajo rendimiento o con daño cerebral. A nivel estructural y molecular, la AEIC estimula del desarrollo de la arborización dendrítica, promueve la neurogénesis en el hipocampo y regula la expresión de genes relacionados con plasticidad, aprendizaje y memoria. Conclusiones: La AEIC en el haz prosencefálico medial, al activar mecanismos de recompensa y de plasticidad neural, constituye un tratamiento prometedor para la mejora de la memoria.(AU)

Intracranial self-stimulation also facilitates learning in a visual discrimination task in the Morris water maze in rats.

Intracranial self-Stimulation (ICSS) of the medial forebrain bundle is a treatment capable of consistently facilitating acquisition of learning and memory in a wide array of experimental paradigms in rats. However, the evidence supporting this effect on implicit memory comes mainly from classical conditioning and avoidance tasks. The present work aims to determine whether ICSS would also improve the performance of rats in another type of implicit task such as cued simultaneous visual discrimination in the Morris Water Maze. The ICSS treatment was administered immediately after each of the five acquisition sessions and its effects on retention and reversal were evaluated 72h later. Results showed that ICSS subjects committed fewer errors than Sham subjects and adopted more accurate trajectories during the acquisition of the task. This improvement was maintained until the probe test at 72h. However, ICSS animals experienced more difficulties than the Sham group during the reversal of the same learning, reflecting an impairment in cognitive flexibility. We conclude that post-training ICSS could also be an effective treatment for improving implicit visual discrimination learning and memory.

Post-training intracranial self-stimulation facilitates a hippocampus-dependent task.

Previous research has shown that post-training intracranial self-stimulation facilitates implicit or procedural memory. To know whether it can also facilitate explicit memory, post-training intracranial self-stimulation was given to Wistar rats immediately after every daily session of a delayed spatial alternation task that seems to depend on the integrity of the hippocampal memory system. We tested the effects of intracranial self-stimulation in three consecutive learning phases which tried to make the task progressively more difficult: 10 s delay (D10 phase), 30 s delay (D30 phase), and inverting the starting position of the animals to make their response more dependent on allocentric cues (INV phase). Every phase finished when each rat achieved a fixed learning criterion. Intracranial self-stimulation facilitated the flexible expression of the learned response (INV phase). That is, when the starting position was randomly inverted, only the rats that received intracranial self-stimulation maintained the performance level acquired in the previous training phases. Changing the starting position reduced the correct performance of the non-treated subjects, which need more training sessions to achieve the learning criterion and made less correct responses than treated rats. These findings show that post-training intracranial self-stimulation can facilitate hippocampus-dependent memories.

Structural plasticity in hippocampal cells related to the facilitative effect of intracranial self-stimulation on a spatial memory task.

Posttraining intracranial self-stimulation (SS) in the lateral hypothalamus facilitates the acquisition and retention of several implicit and explicit memory tasks. Here, intracellular injections of Lucifer yellow were used to assess morphological changes in hippocampal neurons that might be specifically related to the facilitative posttraining SS effect upon the acquisition and retention of a distributed spatial task in the Morris water maze. We examined the structure, size and branching complexity of cornus ammonis 1 (CA1) cells, and the spine density of CA1 pyramidal neurons and granular cells of the dentate gyrus (DG). Animals that received SS after each acquisition session performed faster and better than Sham ones--an improvement that was also evident in a probe trial 3 days after the last training session. The neuromorphological analysis revealed an increment in the size and branching complexity in apical CA1 dendritic arborization in SS-treated subjects as compared with Sham animals. Furthermore, increased spine density was observed in the CA1 field in SS animals, whereas no effects were observed in DG cells. Our results support the hypothesis that the facilitating effect of SS on the acquisition and retention of a spatial memory task could be related to structural plasticity in CA1 hippocampal cells.