Evidence that activation of nuclear peroxisome proliferator-activated receptor alpha (PPARα) modulates sleep homeostasis in rats.

The peroxisome proliferator-activated receptor alpha (PPARα) is a member of the nuclear receptor superfamily that has been suggested as a modulator of several physiological functions. The PPARα recognizes as an endogenous ligand the anorexic lipid mediator oleoylethanolamide (OEA) which displays wake-inducing properties. Despite that recent evidence indicates that activation of PPARα by synthetic agonists such as Wy14643 enhances waking as well as the extracellular contents of wake-related neurotransmitters, the role of PPARα in sleep recovery after prolonged waking has not been fully described. Thus, the aim of this study was to characterize if PPARα regulates sleep rebound after total sleep deprivation (TSD). We report that after 6h of TSD activation of PPARα by pharmacological systemic administration of OEA (10, 20 or 30mg/Kg, i.p.) promoted alertness by blocking the sleep rebound after TSD. Besides, wake-linked compounds such as dopamine, norepinephrine, serotonin, or adenosine collected from nucleus accumbens were enhanced after TSD in OEA-treated animals. These sleep and neurochemical results were mimicked after injection of PPARα agonist Wy14643 (10, 20, 30mg/Kg, i.p.). However, similar findings from the sham of vehicle groups were observed if PPARα antagonist MK-886 was administered to rats (10, 20, 30mg/Kg, i.p.). Our results strengthened the hypothesis that PPARα might modulate sleep and neurochemical homeostasis after sleep deprivation.

Sleep and neurochemical modulation by the nuclear peroxisome proliferator-activated receptor α (PPAR-α) in rat.

The peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear protein that plays an essential role in diverse neurobiological processes. However, the role of PPARα on the sleep modulation is unknown. Here, rats treated with an intrahypothalamic injection of Wy14643 (10µg/1µL; PPARα agonist) enhanced wakefulness and decreased slow wave sleep and rapid eye movement sleep whereas MK-886 (10µg/1µL; PPARα antagonist) promoted opposite effects. Moreover, Wy14643 increased dopamine, norepinephrine, serotonin, and adenosine contents collected from nucleus accumbens. The levels of these neurochemicals were diminished after MK-886 treatment. The current findings suggest that PPARα may participate in the sleep and neurochemical modulation.

Potential effects of cannabidiol as a wake-promoting agent.

Over the last decades, the scientific interest in chemistry and pharmacology of cannabinoids has increased. Most attention has focused on ∆(9)-tetrahydrocannabinol (∆(9)-THC) as it is the psychoactive constituent of Cannabis sativa (C. sativa). However, in previous years, the focus of interest in the second plant constituent with non-psychotropic properties, cannabidiol (CBD) has been enhanced. Recently, several groups have investigated the pharmacological properties of CBD with significant findings; furthermore, this compound has raised promising pharmacological properties as a wake-inducing drug. In the current review, we will provide experimental evidence regarding the potential role of CBD as a wake-inducing drug.

BCL-2 and BAX proteins expression throughout the light-dark cycle and modifications induced by sleep deprivation and rebound in adult rat brain.

It has been suggested that sleep has a restorative function; however, experimental support is limited. Hence, we investigated whether changes in the level of antiapoptotic BCL-2 protein and proapoptotic BAX protein occur during sleep deprivation (SD) and sleep rebound, and evaluated the spontaneous changes in these proteins, along the light-dark cycle, in the adult male Wistar rat. Estimations were made in the prefrontal cortex, hippocampus, striatum, and pons. We observed that BCL-2 exhibited diurnal variations in the prefrontal cortex and striatum, whereas BAX varied in the striatum and showed only small variations in the pons as measured by immunoblotting. The BCL-2/BAX ratio exhibited diurnal variations in the prefrontal cortex and striatum. BCL-2 and BAX levels were affected by 24 hr of total SD and 24 hr of sleep rebound. SD decreased the BCL-2/BAX ratio in the prefrontal cortex and pons. Sleep rebound increased the BCL-2/BAX ratio in the hippocampus. In conclusion, the BCL-2/BAX ratio is high during the dark phase as compared with the light phase in the prefrontal cortex and during the light phase as compared with the dark phase in the striatum. SD decreased the BCL-2/BAX ratio in the prefrontal cortex and pons, whereas sleep rebound increased it in the hippocampus. These changes point out structures in the brain that express these proteins as a response to the light-dark cycle. Similarly, SD and sleep rebound seem to change these proteins expression in some other brain structures, suggesting that cellular vulnerability might be altered by these changes.

Dependencia de los sistemas de memoria al ciclo luz-oscuridad en la expresión de estrategias adaptativas. Segunda parte

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Abstract: In the first part of this work we reviewed the hippocampus and striatum anatomy and function in the context of the memory systems. In this second part we describe the anatomic and physiologic basis of the memory systems represented by the amygdala and prefrontal cortex (PFC) and their participation in the expression of strategies for the solution of specific problems. Amygdaloid formation is divided in three principal regions, the baso-lateral nucleus, the superficial nucleus, and the centromedial nucleus. Amygdala is highly connected with several regions of the brain including hippocampus, striatum and PFC. Amygdala has been implicated in the processing, storing and retrieval of emotional information. Another function proposed for the amygdala is to modulate the activity of structures such as the hippocampus, the striatum and the cerebral cortex. The participation of the amygdala has been shown in different tasks such as the Morris water maze, the radial maze, the passive avoidance task, and the freezing behavior among others. In some of these studies it has been shown that the activation of the amygdala enhances the acquisition of the task. When the amygdala is activated pharmacologically it is able to enhance the acquisition of hippocampus or striatum related tasks. In these context, the efficiency of the amygdala activation depends on the synchrony, the precise time, at which it occurs in relation to the event the subject is learning. This is, either immediately before, during or immediately after learning. In support of this enhancing role of the amygdala, some electrophysiological studies have shown that the activation of the amygdala facilitates the development of LTP in the hippocampus while its lesion decreases it. On the other hand, it has also been shown that the amygdala activation increases c-Fos expression in both, the hippocampus and the striatum. In summary, the amygdaloid formation has been proposed as an enhancer of learning, representing the emotional component of the response to the environment. PFC is the other structure involved in the generation of strategies. It has been related with the correct functioning of higher functions such as memory, attention, emotion, anticipation and planning. It has been called the central executor for its fundamental role as a coordinator of past, present information and future performance. It is been proposed as responsible for the so called working memory, that allows to put together different kinds of information at the same time, giving the chance of comparing, selecting and generating a goaloriented behavior. Working memory has been studied with many different techniques, however electrophysiological experiments have shown interesting aspects of its functioning. Recording cells from the PFC of monkeys, Goldman-Rakic showed that these cells remain firing in a short period of time when visual information should be retained to be used in ulterior comparison task. This cell activity suggests that these neurons would be responsible for the maintenance of information in our "mind" a short period of time. These results have been replicated in humans by using real time imaging techniques as fMRI and PET. Again, during the periods of retention of the information, the activity on prefrontal areas increase until such information is used. Besides working memory, anticipation is another important function regulated by the PFC. Several studies have shown that the activity of prefrontal cortex increases before the performance, it seems like the prefrontal cortex predicts the actions in the environment and readily generates a strategy to efficiently act in response. PFC is connected reciprocally with the hippocampus, the striatum and the amygdala, the relation between these structures is under heavy investigation. Regarding the hippocampus, some interaction has been observed, and it has been proposed an interaction between these structures for the long term consolidation of memory. As for the striatum, the relationship with PFC has been studied preferentially with the ventral striatum or nucleus accumbens with respect to reinforcement of behavior. We understand poorly the relationship with the dorsal striatum. The relation between amygdala and PFC, on the other hand, has been studied in relation to the expectancy of the reinforcement. This is defined as the representation in the mind of the reinforcement and the association of that representation with the conditions under which it was delivered. In simple words, this is a way to explain how is that a subject prefers a specific reinforcer over another. It has been shown that lesions of the basolateral amygdala as well as PFC interfere with the expectancy of reinforcement. The function of the amygdala in this case is to provide the emotional component related to the presence of the reinforcement. An extensive literature has addressed the question of circadian variations in the release of neurotransmitters. For example, the diurnal variations in the release of acetylcholine in the hippocampus and PFC. The binding for acetylcholine, serotonin and norepinephrine to glutamatergic hippocampal cells is different depending on the light-dark cycle, suggesting that the modulation of the hippocampus by these neurotransmitters is different depending on the presence or absence of light. In this review, we have devoted special interest to the influence of the light dark cycle on these mnemonic systems and on goaloriented behaviors. We analyze selected papers from the available literature on circadian rhythms and memory, emphasizing the hippocampus role. We believe that the study of this relationship (brain/light-dark cycle) could be a useful tool to understand how the environment influences behavior. On this topic, there's evidence that the learning of a task may be different depending on the part of the day when it was learned. For example, it has been shown in humans that when subjects are submitted to explicit or implicit task the performance is different depending on the hour of the day, being better during the light for the explicit memory and better during the dark for the implicit memory. Studies in rats trained in fear conditioning tasks, showed that subjects learn the task easily when they are trained during the light phase of the cycle and the learned behavior showed a higher resistance to extinction. Conclusión. When a subject is confronted with a specific problem, he/she can find the solution by using different strategies. The expression of one of those strategies depends on the interaction of the different memory systems, these systems process and storage different kinds of information, and this information is useful to generate and exhibit a given strategy. The memory systems are constantly under the influence of the environment, one critical component of this environment is the lightdark cycle, which apparently is modulating the activity of these structures. As a result of the influence of the light-dark cycle on these structures, the behavior of the subject would be modulated as well. All these interaction just for the sake of adaptation, survival, and reproduction in this rotating and translating world.

Dependencia de los sistemas de memoria al ciclo luz-oscuridad en la expresión de estrategias adaptativas. Primera parte

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Abstract: The ability to abstract, store and recover information from the environment in order to generate new strategies to solve problems is one of the most important qualities of the human brain. We mean by strategy, the sophisticated way to solve a problem. A strategy represents in essence the refinement of a given behavior to solve a problem. A strategy could be generalized to solve different problems. The generation of strategies is subjected to the correct functioning of the brain, meaning, alertness, attention, memory among others brain processes in good stand. In this work we focus on the role of memory in the generation of strategies. In this context, we focus on the literature concerning to memory systems, to show that different memory systems process and store different kinds of information. Therefore, the generation of a given strategy would require the participation of one system instead of other, or at least, one system would be commanding over the others. A memory system is defined as neural network consisting on a central structure communicated through afferences and efferences with others. The ones conveying information to this central structure would provide information from the internal or external environment to be interpreted and stored; while the ones that receive information from the central structure would execute its commands. Curiously, the role of central structure can be played by one structure "A" that in other conditions was under the control of a structure "B". In this condition, "B" is under the control of "A". In this review we sought to describe the anatomic and physiologic basis of the memory systems and their participation in the expression of strategies for the solution of specific problems. In this first part, we review the literature concerning to the hippocampus and striatum. Our endeavor was to make a synthesis of the main components of the functional neuroanatomy of memory and of its specific participation in the generation and expression of strategies, and also of the influence of the light-dark cycle on the strategies resulting from the interaction of these structures. In this review we focus mainly on the basic description of memory systems and on the data obtained from intact rats and of others with lesions and subject to electrophysiological experiments. Many studies reviewed on this first part confront subjects to situations where different solutions can be performed; basically this studies are conducted on mazes were the subject can use different kinds of information for spatial orientation. Depending on the nature of the information available or selected by the subject, investigators may infer the kind of strategy the subject is using to solve the problem. From this background, concepts such as stimulus-stimulus strategy and stimulus-response strategy have been generated. The first one consists of making associations between neutral stimuli, to make a conceptual map that guides the subject toward his/her objective. It has been related with the hippocampus function and it has been classically related to the processing, interpretation, and storage of contexts and events as well as to spatial navigation. We center our attention on studies carried out in mazes, showing that lesions or temporal inactivation of the hippocampus disturb the capacity of orientation by using spatial cues. We also review studies where the expression of spatial strategies is correlated with preferential activation of hippocampus detected with different techniques such as immuno-histochemistry and mycrodialisis in vivo. The stimulus-response strategy, on the other hand, consists on making associations between a particular stimulus and the immediate consequence of its presence. This kind of strategy has been related with the striatum, particularly with its dorsolateral region. For this section we discuss studies where lesions or inactivation of the dorsolateral striatum were performed, on rats submitted to tasks where the solution could be achieved by using stimu-lus-stimulus or stimulus-response strategy. In subjects with striatal dysfunction the ability to perform using a stimulus-response strategy was disrupted but not the ability to use a stimulus-stimu-lus strategy. In addition, we revise studies where the expression of the stimulus-response strategy is correlated with a preferential activation of the striatum over hippocampus. We additionally discuss the interaction hippocampus-striatum to solve a spatial task. We make special emphasis in describing the hippocampal and the striatal systems as independent systems that process and store different kinds of information; therefore, they seem to alternate their activity depending on the demand of the environment. This means that if a stimulus-stimulus strategy is required, the hippocampus will govern the response of the subject, increasing its activity that will be over the activity of the striatum. The opposite will occur if a stimulus-response strategy is required. Studies in humans and rats have been performed to understand the interaction between hippocampus and striatum with similar results. Apparently hippocampus appears more active during the first stages of learning, leading behavior and being expressed as stimulus-stimulus strategy. Later, in learning, the hippocampus decreases in activity and the striatum increases, thus becoming the leader structure. This later activation of stria-tum has been related with the phase of learning when the task is mastered and is starting to become a habit. Finally, we devoted special interest to describe the influence of the light dark cycle over these systems and over the goal-oriented behavior. And as we will see on the second part of this review, the functioning of these structures may be regulated by the light-dark cycle. We will review the influence of the presence or absence of light on neurotransmitters release. We will give evidence indicating that the neurochemical modulation depends greatly on the influence of the light-dark cycle and that it results obviously in a different activity of these structures and hence the behavior. In conclusion, when a subject is confronted with a specific problem, he/she can find the solution by using different strategies. At present, we can not say which are the mechanisms responsible for the selection of a particular strategy at a given mo-ment, but we can say that the expression of any strategy depends on the activity of structures such as the hippocampus and the striatum. In theory each structure represents a memory system or a fundamental part of a memory system. The interaction of the different memory systems, produce a scenario were each system provides, processes, and stores different information about the environment, and this information is useful to generate and exhibit a given strategy. On the second part of this review we will focus on the func-tioning and participation of the amygdala and prefrontal cortex, and the influence of the environment on the memory systems.

RANTES, MDC and SDF-1alpha, prevent the HIVgp120-induced food and water intake decrease in rats.

Human immunodeficiency virus (HIV)-wasting syndrome might be facilitated by the HIVgp120 affecting the immunological system. We studied the effect (subchronic administration: 5 days) of HIVgp120, and a few immune-response mediators: regulated upon activation normal T-cell expressed and presumably secreted (RANTES), stromal derived factor-1alpha (SDF-1alpha), macrophage-derived chemokine (MDC), and their combination, on food and water intake in rats, motor control and pain perception. Eighty male adult Wistar rats received an intracerebroventricular (icv) administration of: vehicle 5 microl/day or 0.92 nmol daily of HIVgp120IIIB, RANTES, SDF-1alpha, or MDC, and the combination of RANTES+HIVgp120IIIB, SDF-1alpha+HIVgp120IIIB, or MDC+HIVgp120IIIB. Food and water intake was measured every day during administration, and 24 and 48 h after the last administration. Rats were also weighed the first and the last day of experiment in order to detect the impact of these treatments in the body weight. HIVgp120IIIB significantly decreased food and water intake. These rats gain less weight than the control (vehicle) and chemokines-treated subjects with exception of those treated with SDF-1alpha that also gain less weight. In addition, HIVgp120 deteriorated motor control. HIVgp120IIIB effects on food and water intake, and motor control were prevented by these chemokines. HIVgp120+RANTES, HIVgp120+SDF-1alpha, and SDF-1alpha alone induced hyperalgesia. Results suggest an interaction between HIVgp120 and the chemokine system to generate the HIV-wasting syndrome, the motor abnormalities and changes in pain perception.

Nicotine prevents HIVgp120-caused electrophysiological and motor disturbances in rats.

Human immunodeficiency virus (HIV)-associated dementia (HAD) is a frequent complication in HIV+ subjects. Several electrophysiological markers and motor control are altered in HIV+ subjects, including event-related potentials (N2-P3 changes). These are electrophysiological indicators of cognitive processing. The mechanisms by which HIV induces neurophysiological abnormality is still under research. However, several neurotransmitters have been implicated. For example, glutamate and the vasoactive intestinal neuropeptide (VIP). In this study, we support further this notion indicating that HIVgp120, a glycoprotein derived from HIV, is involved in the pathogenesis of neuropsychiatric abnormalities. We also have observations suggesting that one HIVgp120 mechanism of action is to interfere with cholinergic neurotransmission. Our results indicate that event-related potentials (ERP) were affected by HIVgp120, in particular N2 and P3. In addition, motor coordination was severely affected. Both parameters were maintained near normality when rats were simultaneously treated with nicotine. These results support further an HIVgp120-caused alteration of cholinergic neurotransmission that might be part of the etiology of neuropsychiatric disturbances.