The posterior insular cortex is necessary for the consolidation of tone fear conditioning.

The insular cortex (IC) is notably implicated in emotional and cognitive processing; however, little is known regarding to what extent its two main subregions play functionally distinct roles on memory consolidation of conditioned fear tasks. Here we verified the effects of temporary functional inactivation of the anterior (aIC) and posterior IC (pIC) on contextual and tone fear memory. Rats received post-training bilateral infusions of the GABAA receptor agonist muscimol into either the aIC or pIC and were tested 48 and 72 h after the delay tone fear conditioning session to assess the background contextual (CFC) and tone (TFC) fear conditioning, respectively. Inactivation of the aIC during memory consolidation did not affect fear memory for CFC or TFC. On the other hand, post-training inactivation of the pIC impaired TFC but not CFC. Our findings indicate that the pIC is a necessary part of the neural circuitry related to the consolidation of cued-fear memories.

A1 adenosine receptors in the striatum play a role in the memory impairment caused by sleep deprivation through downregulation of the PKA pathway.

Sleep deprivation is known to affect memory formation, but how it interacts with different memory systems is not completely understood. Adenosine, a homeostatic regulator of sleep that has an increased extracellular concentration during sleep deprivation, is one of the neuromodulators that may be involved in this interaction. The A1 adenosine receptor is involved in both sleep regulation and memory formation. Among other pathways, the A1 receptor decreases cAMP levels in the cytosol and thus also regulates protein kinase A (PKA) and exchange protein activated by cAMP (EPAC) activity. To verify the role of the A1 receptor in the memory impairment caused by sleep deprivation, we tested the effect of 96 h of sleep deprivation (SD) and the administration of DPCPX, an A1 receptor antagonist on male Wistar rats prior to the training sessions for two memory tasks that relies on the hippocampal function: the multiple trial inhibitory avoidance (MTIA) task, which also requires the striatum, and the contextual fear conditioning (CFC) task, which does not. We also evaluated the effect of SD, DPCPX and the MTIA training session on the protein expression levels of the A1 receptor, PKA phosphorylation and EPAC activity in both the hippocampus and the striatum. Sleep deprivation impaired the performance in the test sessions of both tasks; DPCPX was able to prevent the impairment in the MTIA test but not in the CFC test. SD increased A1 receptor protein expression levels in the striatum but not in the hippocampus and also decreased PKA phosphorylation in both structures; DPCPX prevented this decrease in the striatum, but not in the hippocampus. Finally, SD had no effect on EPAC activity in either of the structures. These results indicate that the A1 adenosine receptors play a role in the memory impairment caused by sleep deprivation in tasks that involve the striatum through modulation of the cAMP/PKA pathway.

The indirect amygdala-dorsal striatum pathway mediates conditioned freezing: insights on emotional memory networks.

The dorsal striatum (DS) is involved in various forms of learning and memory such as procedural learning, habit learning, reward-association and emotional learning. We have previously reported that bilateral DS lesions disrupt tone fear conditioning (TFC), but not contextual fear conditioning (CFC) [Ferreira TL, Moreira KM, Ikeda DC, Bueno OFA, Oliveira MGM (2003) Effects of dorsal striatum lesions in tone fear conditioning and contextual fear conditioning. Brain Res 987:17-24]. To further elucidate the participation of DS in emotional learning, in the present study, we investigated the effects of bilateral pretest (postraining) electrolytic DS lesions on TFC. Given the well-acknowledged role of the amygdala in emotional learning, we also examined a possible cooperation between DS and the amygdala in TFC, by using asymmetrical electrolytic lesions, consisting of a unilateral lesion of the central amygdaloid nucleus (CeA) combined to a contralateral DS lesion. The results show that pre-test bilateral DS lesions disrupt TFC responses, suggesting that DS plays a role in the expression of TFC. More importantly, rats with asymmetrical pre-training lesions were impaired in TFC, but not in CFC tasks. This result was confirmed with muscimol asymmetrical microinjections in DS and CeA, which reversibly inactivate these structures. On the other hand, similar pretest lesions as well as unilateral electrolytic lesions of CeA and DS in the same hemisphere did not affect TFC. Possible anatomical substrates underlying the observed effects are proposed. Overall, the present results underscore that other routes, aside from the well-established CeA projections to the periaqueductal gray, may contribute to the acquisition/consolidation of the freezing response associated to a TFC task. It is suggested that CeA may presumably influence DS processing via a synaptic relay on dopaminergic neurons of the substantia nigra compacta and retrorubral nucleus. The present observations are also in line with other studies showing that TFC and CFC responses are mediated by different anatomical networks.

Protein synthesis inhibition in the basolateral amygdala following retrieval does not impair expression of morphine-associated conditioned place preference.

Conditioned place preference is an animal model used to evaluate the affective properties of natural rewards and drugs of abuse. This animal model is a kind of classical conditioning that depends on learning and memory. The basolateral amygdala (BLA) plays an important role in the consolidation and extinction of memory for this task. However, there is a lack of evidence demonstrating protein synthesis dependent reconsolidation following retrieval in conditioned animals. In other words, is it possible to observe morphine-associated place preference if recall of this preference is disrupted? Accordingly, we investigated this hypothesis by BLA infusion of protein synthesis inhibitor, anisomycin, immediately after retrieval (test) in conditioned place preference paradigm. In the first experiment, the conditioned animals were exposed to the two sides of the apparatus for 15 min in a drug-free state during retrieval. In the second experiment, the animals received an injection of morphine (7.5 mg/kg, i.p.) and immediately after, they were exposed to the two sides of the apparatus for 15 min. Finally in the third experiment, after habituation and training in the conditioned place preference task, the animals received an injection of the unconditioned stimulus (morphine, i.p.; 7.5 mg/kg) followed by confinement for 10 min in the morphine-paired compartment (conditioned stimulus) during memory retrieval. For the three experiments the animals were subsequently exposed in a free-drug state to the two sides of the apparatus for the retest. Our results show that the protein synthesis inhibition in all of these experimental designs had no effect on conditioned place preference memory under conditions that would initiate reconsolidation, suggesting that if reconsolidation of a conditioned place preference task exists it is not mediated by protein synthesis in basolateral amygdala. The effect of anisomycin on consolidation of contextual fear conditioning was also investigated as a positive control to assure that the negative results were not due to methodological problems. Using the same dose of anisomycin (62.5 microg/1 microl) in morphine-associated place preference procedures, we have found that this anisomycin dose blocks the consolidation of contextual fear memory, ruling out the possibility that these negative results can be attributed to methodological problem of some sort.

Heteropterys aphrodisiaca (extract BST0298): a Brazilian plant that improves memory in aged rats.

Literature report is lacking on pharmacological studies of the plant Heteropterys aphrodisiaca, endemic to the scrublands of Brazil. The present study was carried out to investigate the effects of oral dosing with extract BST0298 from this plant, on learning and on memory, in young (3-6-month-old) and aged (20-28-month-old) rats. The aged animals presented significant memory deficits in both the passive avoidance and T-maze left/right discrimination tests. Treatment for 7 days (50 mg/kg) or 26 days (100 mg/kg) with extract BST0298 restored the memory deficits in the passive avoidance test. However, no improvement in memory was observed after acute administration of extract BST0298 (100 mg/kg) in aged rats. An improvement in learning was also observed in the left/right discrimination test in aged rats treated for 109 days with BST0298 at a dose of 50 mg/kg. These results suggest that treatment for 7 days or more with H. aphrodisiaca improves learning and memory deficits in aged rats.

Spatial memory is improved by aerobic and resistance exercise through divergent molecular mechanisms.

A growing body of scientific evidence indicates that exercise has a positive impact on human health, including neurological health. Aerobic exercise, which is supposed to enhance cardiovascular functions and metabolism, also induces neurotrophic factors that affect hippocampal neurons, thereby improving spatial learning and memory. Alternatively, little is known about the effect of resistance exercise on hippocampus-dependent memory, although this type of exercise is increasingly recommended to improve muscle strength and bone density and to prevent age-related disabilities. Therefore, we evaluated the effects of resistance training on spatial memory and the signaling pathways of brain-derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF-1), comparing these effects with those of aerobic exercise. Adult male Wistar rats underwent 8 weeks of aerobic training on a treadmill (AERO group) or resistance training on a vertical ladder (RES group). Control and sham groups were also included. After the training period, both AERO and RES groups showed improved learning and spatial memory in a similar manner. However, both groups presented distinct signaling pathways. Although the AERO group showed increased level of IGF-1, BDNF, TrkB, and ß-CaMKII (calcium/calmodulin-dependent kinase II) in the hippocampus, the RES group showed an induction of peripheral and hippocampal IGF-1 with concomitant activation of receptor for IGF-1 (IGF-1R) and AKT in the hippocampus. These distinct pathways culminated in an increase of synapsin 1 and synaptophysin expression in both groups. These findings demonstrated that both aerobic and resistance exercise can employ divergent molecular mechanisms but achieve similar results on learning and spatial memory.

Resistance exercise improves hippocampus-dependent memory.

It has been demonstrated that resistance exercise improves cognitive functions in humans. Thus, an animal model that mimics this phenomenon can be an important tool for studying the underlying neurophysiological mechanisms. Here, we tested if an animal model for resistance exercise was able to improve the performance in a hippocampus-dependent memory task. In addition, we also evaluated the level of insulin-like growth factor 1/insulin growth factor receptor (IGF-1/IGF-1R), which plays pleiotropic roles in the nervous system. Adult male Wistar rats were divided into three groups (N = 10 for each group): control, SHAM, and resistance exercise (RES). The RES group was submitted to 8 weeks of progressive resistance exercise in a vertical ladder apparatus, while the SHAM group was left in the same apparatus without exercising. Analysis of a cross-sectional area of the flexor digitorum longus muscle indicated that this training period was sufficient to cause muscle fiber hypertrophy. In a step-through passive avoidance task (PA), the RES group presented a longer latency than the other groups on the test day. We also observed an increase of 43 and 94% for systemic and hippocampal IGF-1 concentration, respectively, in the RES group compared to the others. A positive correlation was established between PA performance and systemic IGF-1 (r = 0.46, P < 0.05). Taken together, our data indicate that resistance exercise improves the hippocampus-dependent memory task with a concomitant increase of IGF-1 level in the rat model. This model can be further explored to better understand the effects of resistance exercise on brain functions.

Acute systemic blockade of D2 receptors does not accelerate the extinction of cocaine-associated place preference.

Facilitation of extinction can be used as a therapeutic tool in treatment of both post-traumatic stress disorder and drug addiction. The present study examined whether the blockade of D2 receptors before each extinction trial would accelerate the extinction of cocaine-induced place preference. Male Wistar rats were initially conditioned and tested for a cocaine-associated place-preference (20 mg/kg). On the following day after the initial test, the animals were submitted to extinction training. This training consisted of daily sessions in which the subjects were alternatively confined during 30 min in the saline and cocaine-associated environment. However, 30 min before each extinction trial the animals received a systemic injection of D2 antagonist sulpiride. While one group was treated with a dose of 50 mg/kg (ip), the other group was treated with a dose of 100 mg/kg. An additional control group received injections of saline during extinction trials. Twenty-four hours after the last extinction trial, the animals were tested again for their preferences to cocaine and saline associated environments. Since one round of extinction trial was not sufficient to produce extinction of cocaine associated place preference, the animals were submitted to a second cycle of extinction trials and test. The systemic administration of the two doses of sulpiride (50 and 100 mg/kg) 30 min before each conditioning did not enhance the extinction of cocaine-associated place preference. This finding suggests that the D2 receptors are not involved in a acute protocol of extinction of cocaine-induced place preference.

Resistance exercise improves hippocampus-dependent memory

It has been demonstrated that resistance exercise improves cognitive functions in humans. Thus, an animal model that mimics this phenomenon can be an important tool for studying the underlying neurophysiological mechanisms. Here, we tested if an animal model for resistance exercise was able to improve the performance in a hippocampus-dependent memory task. In addition, we also evaluated the level of insulin-like growth factor 1/insulin growth factor receptor (IGF-1/IGF-1R), which plays pleiotropic roles in the nervous system. Adult male Wistar rats were divided into three groups (N = 10 for each group): control, SHAM, and resistance exercise (RES). The RES group was submitted to 8 weeks of progressive resistance exercise in a vertical ladder apparatus, while the SHAM group was left in the same apparatus without exercising. Analysis of a cross-sectional area of the flexor digitorum longus muscle indicated that this training period was sufficient to cause muscle fiber hypertrophy. In a step-through passive avoidance task (PA), the RES group presented a longer latency than the other groups on the test day. We also observed an increase of 43 and 94% for systemic and hippocampal IGF-1 concentration, respectively, in the RES group compared to the others. A positive correlation was established between PA performance and systemic IGF-1 (r = 0.46, P < 0.05). Taken together, our data indicate that resistance exercise improves the hippocampus-dependent memory task with a concomitant increase of IGF-1 level in the rat model. This model can be further explored to better understand the effects of resistance exercise on brain functions.

Recognition memory for emotional pictures in Alzheimer's patients.

OBJECTIVE: The purpose of the present study was to examine whether Alzheimer's Disease (AD) patients can benefit from the emotional content of visual stimuli in a picture recognition test. METHODS: Sixteen patients with AD and 19 normal controls matched for age and years of education, were studied. Sixteen pictures (with varying emotional contents) were presented to each participant. Thirty minutes later, a recognition test was applied with the target-pictures mixed among 34 others of similar content. The subjects were instructed to rate them as pleasant, unpleasant or indifferent. RESULTS: The total of pictures correctly recognized by the AD patients (75.4% of the target-pictures) was smaller than that of the controls (96.4%). Controls recognized more emotional pictures than indifferent pictures. CONCLUSION: Emotional content enhanced recognition of pictures in normal subjects, whereas for the Alzheimer's subjects the emotional significance attached to the pictures was of no benefit to enhance recognition.

Is behavioral sensitization to ethanol associated with contextual conditioning in mice?

Behavioral sensitization to drugs of abuse seems to involve learning processes. In mice, ethanol-induced locomotor sensitization is potentiated by repeated pairing of ethanol (EtOH) injections and the testing chamber. The present study aimed to test: (1). the association between the performance in a contextual conditioning task and the development of behavioral sensitization to EtOH in mice; (2). whether EtOH sensitization would be expressed in a different testing environment. Male albino Swiss mice (n=72) were initially submitted to a contextual fear conditioning task. After 2 weeks without manipulation, the animals received daily i.p. injections of 2.2 g/kg EtOH (n=52) or saline (n=20), for 21 days. They were tested weekly for locomotor activity in activity cages. After 1 week of withdrawal, all mice received 2.2 g/kg EtOH and had their locomotor activity recorded in an open-field. According to the locomotor behavior displayed along the 21-day treatment, EtOH-treated mice were classified as sensitized (n=15) or non-sensitized (n=15). When these subgroups and saline-treated mice were compared for the freezing response in the conditioning test, sensitized mice displayed a greater freezing time than non-sensitized mice. When challenged with EtOH in the open-field, none of the EtOH-treated subgroups expressed behavioral sensitization. These results suggest that the development of EtOH sensitization seems to be positively associated with contextual learning, and further confirms that the expression of sensitization is highly dependent on contextual cues.

Anterograde effects of a single electroconvulsive shock on inhibitory avoidance and on cued fear conditioning

A single electroconvulsive shock (ECS) or a sham ECS was administered to male 3-4-month-old Wistar rats 1,2, and 4 h before training in an inhibitory avoidance test and in cued classical fear conditioning (measured by means of freezing time in a new environment). ECS impaired inhibitory avoidance at all times and, at 1 or 2 h before training, reduced freezing time before and after re-presentation of the ECS. These results are interpreted as a transient conditioned simulus (CS)-induced anxiolytic or analgesic effect lasting about 2 h after a single treatment, in addition to the known amnesic effect of the stimulus. This suggests that the effect of anterograde learning impairement is demonstrated unequivocally only when the analgesic/anxiolytic effect is over (about 4 h after ECS administration) and that this impairment of learning is selective, affecting inhibitory avoidance but not classical fear conditioning to a discrete stimulus.

Ethanol decreases choice accuracy in a radial maze delayed test

1. The effect of acute ethanol on memory was studied in an eight-arm radial maze by interposing a 15-s or 1-h delay between the rat's fourth and fifth arma choices. 2. Ethanol (1.0g/Kg) was injected intraperitoneally 5 min prior to the firsrt set of 4-arm choices, therefore being presrnt since the acquisition of the trial-unique event. 3. The results showed 1) a decrease in choice accuracu only in the final 4 arm choices after the 1-h delay, and 2) that errors consisted of re-entries into arms chosen before the delay was imposed. The data further support the contention that ethanol impairs retention of working memory