Performance in working memory and attentional control is associated with the rs2180619 SNP in the CNR1 gene.

Individual differences in cognitive performance are partly dependent, on genetic polymporhisms. One of the single-nucleotide polymorphisms (SNP) of the CNR1 gene, which codes for cannabinoid receptor 1 (CB1R), is the rs2180619, located in a regulatory region of this gene (6q14-q15). The alleles of the rs2180619 are A > G; the G allele has been associated with addiction and high levels of anxiety (when the G allele interacts with the SS genotype of the 5-HTTLPR gene). However, GG genotype is observed also in healthy subjects. Considering G allele as risk for 'psychopathological conditions', it is possible that GG healthy subjects do not be addicted or anxious, but would have reduced performance, compared to AA subjects, in attentional control and working memory processing. One hundred and sixty-four healthy young Mexican-Mestizo subjects (100 women and 64, men; mean age: 22.86 years, SD=2.72) participated in this study, solving a task where attentional control and working memory were required. GG subjects, compared to AA subjects showed: (1) a general lower performance in the task (P = 0.02); (2) lower performance only when a high load of information was held in working memory (P = 0.02); and (3) a higher vulnerability to distractors (P = 0.03). Our results suggest that, although the performance of GG subjects was at normal levels, a lower efficiency of the endocannabinoid system, probably due to a lowered expression of CB1R, produced a reduction in the performance of these subjects when attentional control and working memory processing is challenged.

De la restauración neuronal a la reorganización de los circuitos neuronales: una aproximación a las funciones del sueño / From neuronal recovery to the reorganisation of neuronal circuits: a review of the functions of sleep

Objetivo. Analizar datos y conceptos que se han generadoen torno a una de las funciones propuestas para el sueño: la restauraciónneuronal. Desarrollo. El sueño es un estado de concienciadiferente de la vigilia. Los mamíferos invierten una buena partede su vida en dormir; por ejemplo, los humanos dormimos una terceraparte de nuestra vida, pero ¿para qué invertir tanto tiempo enun estado donde perdemos contacto con el entorno?, ¿qué pasaríasi no durmiéramos? La privación de sueño total altera procesoscognitivos, como la memoria o la atención; si esta privación seprolonga, el sujeto se deteriora y muere. Se ha propuesto que elsueño sirve para restaurar a los organismos del desgaste ocurridodurante la vigilia y, dado que los primeros efectos de la ausenciade sueño se observan en procesos que dependen directamente delcerebro, se ha sugerido que la restauración neuronal es su principalobjetivo. En este trabajo se analizan algunos estudios sobre losefectos de la privación de sueño total en humanos y ratas, así comola relación entre el sueño y el sistema de las neurotrofinas, el cualpromueve la supervivencia y la restauración neuronal. Finalmente,se discuten teorías recientes sobre la función del sueño. Conclusiones.La restauración de las neuronas no es el fin último del sueño,sino mantener y reorganizar los circuitos neuronales, incluyendo laneoformación de sinapsis, que permiten modificar redes neuronalesexistentes, por efecto de la experiencia, y todo esto para el adecuadofuncionamiento del cerebro y su adaptación al ambiente

Aim. To analyse the data and concepts that have been produced in relation to one of the functions that have beensuggested for sleep, namely, neuronal recovery. Development. Sleep is a state of consciousness that is different to that ofarousal. Mammals devote an important part of their lives to sleeping; for example, as humans, we sleep for a third of our lives,but why do we spend so much time in a state where we lose contact with our surroundings? What would happen if we didn’tsleep? Total sleep deprivation alters cognitive processes such as memory or attention, and if this deprivation is prolonged, theindividual deteriorates and dies. It has been suggested that sleep provides the organism with time to recover from the wear andtear that occurs during the waking state and, given that the first effects of the absence of sleep are seen to affect processes thatare directly dependent on the brain, it has been claimed that its main purpose is to allow neuronal recovery. In this work weanalyse some of the studies on the effects of total sleep deprivation in humans and rats, as well as the relationship betweensleep and the neurotrophin system, which promotes neuronal survival and recovery. Finally, the latest theories about thefunction of sleep are discussed. Conclusions. Neuron recovery is not the ultimate purpose of sleep; rather it is to allow formaintenance and reorganisation of neuronal circuits, including new synapse formation, which enables existing neuronalnetworks to be modified by the effect of experience, and all this makes it possible for the brain to work properly and to adaptitself to the environment

[From neuronal recovery to the reorganisation of neuronal circuits: a review of the functions of sleep]. / De la restauración neuronal a la reorganización de los circuitos neuronales: una aproximación a las funciones del sueño.

AIM: To analyse the data and concepts that have been produced in relation to one of the functions that have been suggested for sleep, namely, neuronal recovery. DEVELOPMENT: Sleep is a state of consciousness that is different to that of arousal. Mammals devote an important part of their lives to sleeping; for example, as humans, we sleep for a third of our lives, but why do we spend so much time in a state where we lose contact with our surroundings? What would happen if we didn't sleep? Total sleep deprivation alters cognitive processes such as memory or attention, and if this deprivation is prolonged, the individual deteriorates and dies. It has been suggested that sleep provides the organism with time to recover from the wear and tear that occurs during the waking state and, given that the first effects of the absence of sleep are seen to affect processes that are directly dependent on the brain, it has been claimed that its main purpose is to allow neuronal recovery. In this work we analyse some of the studies on the effects of total sleep deprivation in humans and rats, as well as the relationship between sleep and the neurotrophin system, which promotes neuronal survival and recovery. Finally, the latest theories about the function of sleep are discussed. CONCLUSIONS: Neuron recovery is not the ultimate purpose of sleep; rather it is to allow for maintenance and reorganisation of neuronal circuits, including new synapse formation, which enables existing neuronal networks to be modified by the effect of experience, and all this makes it possible for the brain to work properly and to adapt itself to the environment.

Dissociation between adipose tissue signals, behavior and the food-entrained oscillator.

Digestive and metabolic processes are entrained by restricted feeding (RFS) schedules and are thought to be potential elements of a food-entrained oscillator (FEO). Due to the close relationship of leptin with metabolic regulation and because leptin is a relevant communication signal of the individual's peripheral metabolic condition with the central nervous system, we explored whether leptin is an endogenous entraining signal from the periphery to a central element of an FEO. First we characterized in the rat the diurnal rhythm of serum leptin (in rats fed ad libitum (AL)), its adjustment to an RFS and the influence of fasting after RFS, or RFS followed by AL feeding and then total food deprivation (RF-AF) in the persistence of this fluctuating pattern. We also explored the response of free fatty acids and stomach weight under the same entraining conditions. We compared the metabolic response with the behavioral expression of drinking anticipatory activity (AA) under the same conditions. Finally, we tested the effect of daily i.c.v administration of leptin as a putative entraining signal for the generation of AA. Metabolic parameters responded to food entrainment by adjusting their phase to mealtime. However, leptin and free fatty acid rhythms persisted only for a few cycles in fasting conditions and readjusted to the light-darkness cycle after an RF-AF protocol. In contrast, behavioral food-entrained rhythms persisted after both fasting manipulations. Daily leptin i.c.v. administration did not produce AA, nor produce changes in the behavioral free-running rhythm. Stomach weight indicated an adaptive process allowing an extreme stomach distension followed by a slow emptying process, which suggests that the stomach may be playing a relevant role as a storage organ. In conclusion, metabolic signals here studied respond to feeding schedules by adjusting their phase to mealtime, but do only persist for a few cycles in fasting. Leptin does not produce AA and thus is not an entraining signal for FEO. The response of metabolic signals to feeding schedules depends on different mechanisms than the expression of AA.

Liver 5'-deiodinase activity is modified in rats under restricted feeding schedules: evidence for post-translational regulation.

Restricted feeding schedules (RFSs) produce a behavioral activation known as anticipatory activity, which is a manifestation of a food-entrained oscillator (FEO). The liver could be playing a role in the physiology of FEO. Here we demonstrate that the activity of liver selenoenzyme deiodinase type 1 (D1), which transforms thyroxine into triiodothyronine (T3), decreases before food access and increases after food presentation in RFSs. These changes in D1 activity were not due to variations in D1 mRNA. In contrast, a 24 h fast promoted a decrease in both D1 activity and mRNA content. The adjustment in hepatic D1 activity was accompanied by a similar modification in T3-dependent malic enzyme, suggesting that the local generation of T3 has physiological implications in the liver. These results support the notion that the physiological state of rats under RFSs is unique and distinct from rats fed freely or fasted for 24 h. Data also suggest a possible role of hepatic D1 enzyme in coordinating the homeorhetic state of the liver when this organ participates in FEO expression.

Role of cholecystokinin-A and cholecystokinin-B receptors in anxiety.

Evidence from several laboratories indicates that the anxiogenic effects of cholecystokinin (CCK) are mediated by CCKB receptors. However, it has been reported that CCKA receptors have been found in brain and CCKA antagonists have anxiolytic properties. The aim of this work was to study whether CCKA receptors are also involved in the modulation of anxiety. Anxiogenic effects were observed in the elevated plus maze in rats when pure CCKB receptor agonists (CCK-4 and CCK-8 non-sulfated) or CCK-8S, a CCKB/CCKA agonist, were injected into the lateral ventricle. In contrast, CCK-33, a CCKA agonist or CCK-(1-21) and CCK-(26-29) were ineffective. Furthermore, the anxiogenic effects of CCK-8S were prevented by blocking CCKB but not CCKA receptors. Finally, CCK-33 injected into the postero-medial nucleus accumbens failed to affect the anxiety level of the rats. These results indicate that CCKA receptors are not involved in anxiety, as measured by the paradigms used in this work.

The brain decade in debate: IV. Chronobiology.

The present article is the adapted version of an electronic symposium organized by the Brazilian Society of Neuroscience and Behavior (SBNeC) which took place on June 14, 2000. The text is divided into three sections: I. The main issues, II. Chronodrugs, and III. Methods. The first section is dedicated to the perspectives of chronobiology for the next decade, with opinions about the trends of future research being emitted and discussed. The second section deals mostly with drugs acting or potentially acting on the organism's timing systems. In the third section there are considerations about relevant methodological issues concerning data analysis.

The brain decade in debate: IV. Chronobiology

The present article is the adapted version of an electronic symposium organized by the Brazilian Society of Neuroscience and Behavior (SBNeC) which took place on June 14, 2000. The text is divided into three sections: I. The main issues, II. Chronodrugs, and III. Methods. The first section is dedicated to the perspectives of chronobiology for the next decade, with opinions about the trends of future research being emitted and discussed. The second section deals mostly with drugs acting or potentially acting on the organism's timing systems. In the third section there are considerations about relevant methodological issues concerning data analysis

Anticipatory changes in liver metabolism and entrainment of insulin, glucagon, and corticosterone in food-restricted rats.

Restricted feeding schedules entrain behavioral and physiological circadian rhythms, which depend on a food-entrainable oscillator (FEO). The mechanism of the FEO might depend on digestive and endocrine processes regulating energy balance. The present study characterizes the dynamics of circulating corticosterone, insulin, and glucagon and regulatory parameters of liver metabolism in rats under restricted feeding schedules. With respect to ad libitum controls, food-restricted rats showed 1) an increase in corticosterone and glucagon and a decrease in insulin before food access, indicating a predominant catabolic state; and 2) a reduction in lactate-to-pyruvate and beta-hydroxybutyrate-to-acetoacetate ratios, indicating an oxidized cytoplasmic and mitochondrial redox state in the liver metabolism. All these changes were reversed after feeding. Moreover, liver energy charge in food-restricted rats did not show a significant modification before feeding, despite an increase in adenine nucleotides, but showed an important decrease after food intake. Variations detected in the liver of food-restricted rats are different from those prevailing under 24-h fasting. These observations suggest "anticipatory activity" of the liver metabolism to optimize the processing of nutrients to daily feeding. Data also suggest a possible relationship of the liver and endocrine signals with the FEO.

Metabolic correlates of the circadian pattern of suckling-associated arousal in young rabbits.

Young rabbits (Oryctolagus cuniculus) are only nursed for 3-5 min every 24 h. They show a circadian increase in activity in anticipation of this, which is entrained by suckling. Our aim was to determine whether serum and liver metabolites show diurnal fluctuations which could act to regulate this circadian pattern. Stomach weight, liver glycogen and serum metabolites were measured every 3 h in 7- to 8-day-old pups when normally nursed (up to 24 h after suckling) and fasted (up to 48 h after suckling). The results suggest: 1. Energy balance between feeds was maintained by a cascade in the use of fuels, first glucose from the milk, then glycogen stores and gluconeogenesis from circulating products of proteins and triglycerides, and finally, in late-fasted animals, the mobilization of free fatty acids. 2. The empty stomach and depletion of glycogen 23-24 h after the last feed could act to trigger anticipatory arousal in normally nursed pups, and the release of free fatty acids 45 48 h after the last feed could trigger this in fasted pups. 3. Unmasking of rhythmicity by fasting in serum levels of glucose and proteins suggests their regulation by endogenous oscillators, which may also be the case for the mobilization of free fatty acids.

Circadian modulation of the ryanodine receptor type 2 in the SCN of rodents.

We examined the temporal modulation of intracellular calcium release channels in the suprachiasmatic nucleus (SCN). We found a circadian rhythm in [3H]ryanodine binding that was specific to the SCN. The peak in the rhythm occurred at CT 7 and was due to an increase in Bmax, which correlated well with immunoblots showing an increase in RyR-2 expression in the SCN. Double immunohistochemical studies showed that RyR-2 was expressed exclusively in neurons. Ryanodine and caffeine applied around CT 7-9 advanced the clock phase in a hamster brain slice preparation. No rhythm of IP3R was seen in any of the brain areas studied. Our results indicate that RyR-2 exhibits an endogenous rhythm, which influences the intracellular calcium dynamics and thus modulates SCN activity.

Effects of Protein Malnutrition on Vigilance States and their Circadian Rhythms in 30-Day-Old Rats Submitted Total Sleep Deprivation.

This study examined how chronic protein malnutrition (6% casein diet) affected the electrocorticogram (ECoG) in young rats following 24 h of sleep deprivation. Baseline (basal day) ECoG-polygraphic recordings were obtained in Sprague-Dawley rats after which animals were sleep-deprived for 24 h by means of a slowly rotating cylinder. ECoG recordings were subsequently obtained for a further three days of recovery. Body weight was significantly reduced in malnourished rats from postnatal day 4 until 34. On basal day, malnourished rats showed a significant increase of slow wave sleep (SWS) during the light and dark phases of the circadian period, and over the 24 h of recording in comparison to control rats. Also, rapid eye movement sleep (REMS) was significantly increased in these rats during the 12-h dark phase of basal day, but wake ECoG activity was significantly reduced during both light and dark phases and over the 24 h of recording, as a result of sleep increases. After sleep deprivation, young malnourished rats failed to show any significant SWS rebound and, unlike control rats, they did not regain pre-deprivation SWS levels within the 3-day post-deprivation recovery period. Further, malnourished rats also failed to have a significant REMS rebound, especially during the dark phase. These results show an important alteration produced by protein malnutrition in the homeostatic and circadian control of vigilance states before and after sleep deprivation.

Correlation between blood adenosine metabolism and sleep in humans.

Blood adenosine metabolism, including metabolites and metabolizing enzymes, was studied during the sleep period in human volunteers. Searching for significant correlations among biochemical parameters found: adenosine with state 1 of slow-wave sleep (SWS); activity of 5'-nucleotidase with state 2 of SWS; inosine and AMP with state 3-4 of SWS; and activity of 5'-nucleotidase and lactate with REM sleep. The correlations were detected in all of the subjects that presented normal hypnograms, but not in those who had fragmented sleep the night of the experiment. The data demonstrate that it is possible to obtain information of complex brain operations such as sleep by measuring biochemical parameters in blood. The results strengthen the notion of a role played by adenosine, its metabolites and metabolizing enzymes, during each of the stages that constitute the sleep process in humans.

Sexual behavior in sleep, sleepwalking and possible REM behavior disorder: a case report.

Seven cases of sexual behavior during sleep (SBS) have been recently reported. The subjects had histories of behavioral parasomnias as well as positive family histories of parasomnia. A 27 year-old man with a history of sexual behavior during sleep was reported. His sleep history disclosed sleepwalking (SW) since 9 years of age. He also developed episodes of highly disruptive and violent nocturnal behavior with dream enactment at age 20 years, which often resulted in physical injuries either to himself or his wife and infant. His wife also reported episodes of amnestic sexual behavior that began 4 years before referral. During the episodes, the patient typically procured his wife, achieving complete sexual intercourse with total amnesia. Physical and neurological diagnostic workups were unremarkable. Family history disclosed sleepwalking in his brother. He was put on 2mg/day of bedtime clonazepam with a remarkable clinical improvement. This case involves either the combination of violent and non-violent sleepwalking with SBS, or the superimposition of presumed REM sleep behavior disorder (RBD) on top of preexisting SW in a man who also developed SBS in adulthood. Thus, this is a case report of probable parasomnia overlap syndrome.

The sensory but not muscular pelvic nerve branch is necessary for parturition in the rat.

In the rat the pelvic nerve consists of a viscerocutaneous (sensory) branch which receives information from pelvic viscera and the midline perineal region, and a somatomotor (muscular) branch which innervates the ilio- and pubococcygeous muscles. To investigate the contribution of these branches to the parturition process, the length of gestation and course of delivery were closely monitored in 43 pregnant, Wistar-strain rats randomly assigned to five groups: untreated control animals, animals in which the somatomotor branch of the pelvic nerve was bilaterally sectioned on Day 14 of gestation, animals in which the viscerocutaneous branch of the pelvic nerve was bilaterally sectioned on Day 14 of gestation, animals treated similarly to the previous group but with young delivered by C-section at term, and sham-operated controls. Sectioning the viscerocutaneous branch seriously disrupted parturition and resulted in major dystocia and a high percentage of stillbirths in all females. In contrast, sectioning the somatomotor branch had no apparent effect on parturition and no significant differences were found between females of this group and sham or control dams on any of the measures recorded. It is concluded that the viscerocutaneous branch of the pelvic nerve is vital for the normal course of parturition in the rat but that the somatomotor branch plays little role, if any.

The siesta culture concept is not supported by the sleep habits of urban Mexican students.

Evidence in support for the concept of the so-called 'siesta culture' is not well developed and has, to date, relied largely on qualitative anthropological data. Presumably such cultures are characterized by a strong tendency for daytime naps and daytime sleepiness, phenomena which may partially represent the effects of geographic, climatic or light conditions and/or cultural influences. In this study we surveyed the nocturnal sleep habits and daytime sleep tendencies of 577 Mexican college students residing in Mexico City (19 degrees N latitude). Results indicated a number of parallels between the reported sleep habits of these students and those reported from other cultures at latitudes far to the north (North America, Europe), such as longer sleep at the weekends, an association between snoring and daytime sleepiness and a lack of relationship between nocturnal sleep duration and the reported tendency to nap. There was some suggestion that these Mexican students may actually nap less when compared to other college student populations. Taken together, these results call into question what is meant by the concept of a 'siesta culture', at least in this urban, educated, upper social economic scale (SES) population, and suggest that future studies in equatorial regions be undertaken to further appreciate the role of climate, photoperiod and/or culture in the tendency for humans to nap during the day.

Persistence of metabolic rhythmicity during fasting and its entrainment by restricted feeding schedules in rats.

The presence of a food-entrainable oscillator (FEO) independent from the SCN is now well established, but until now its location and characterization have been elusive. Because its expression requires priming of the animal's metabolism toward a catabolic state, it is possible that metabolic rhythms may be related to FEO. The present study was designed to determine whether metabolic rhythms persist during fasting and whether such rhythms could be entrained to a restricted feeding schedule. The results indicate persistent rhythms of triacylglycerides, free fatty acids, glucose, and proteins during fasting, whereas ketone bodies and liver glycogen changed their concentration as a function of fasting. Daily food pulses of 2 h entrained the rhythms of triacylglycerides and free fatty acids and restored ketone bodies and liver glycogen to similar levels as controls. Neither glucose nor proteins were affected by the food pulse. These results indicate the relevance of lipid metabolism as a phenomenon associated with the FEO.

Organization of circadian rhythmicity and suprachiasmatic nuclei in malnourished rats.

The present study was aimed at characterizing the effects of low-protein malnutrition (6% casein) on the circadian rhythm of drinking behavior and on suprachiasmatic nuclei immunohistochemistry in Sprague-Dawley rats. Recordings were started at 30 days of age under a 12:12-h light-dark (LD) cycle. At age 150 days, recordings were continued under constant dim red light, and finally the latency to entrain to complete and skeleton photoperiods was established. At the end of the recordings rats were processed for histological analysis. Compared with their controls, malnournished rats exhibited 1) splitting of rhythmicity under LD that 2) condensed to one component in constant dim red light, 3) delayed entrainment to skeleton photoperiod, and 4) precocious entrainment under complete photoperiod. Immunohistochemical analysis showed mainly a decrease in the immunohistochemical detection of vasoactive intestinal polypeptide and glial fibrillar acid protein cells in malnourished animals. These results indicate that in malnourished rats there is a decrease 1) in the coupling force among the oscillators and 2) in the strength of the phase lock between the oscillators and the light-dark cycle.