Ketamine anesthesia enhances fear memory consolidation via noradrenergic activation in the basolateral amygdala.

Trauma patients treated with ketamine during emergency care present aggravated early post- traumatic stress reaction which is highly predictive of post-traumatic stress disorder (PTSD) development and severity. The use of ketamine in the acute trauma phase may directly or indirectly interfere with neural processes of memory consolidation of the traumatic event, thus leading to the formation of maladaptive memories, a hallmark symptom of PTSD. We have recently shown that ketamine anesthesia, immediately after a traumatic event, enhances memory consolidation and leads to long-lasting alterations of social behavior in rats. Based on the evidence that ketamine induces a robust central and peripheral adrenergic/noradrenergic potentiation and that activation of this system is essential for the formation of memory for stressful events, we explored the possibility that the strong sympathomimetic action of ketamine might underlie its memory enhancing effects. We found that rats given immediate, but not delayed, post-training ketamine anesthesia (125 mg/kg) presented enhanced 48-h memory retention in an inhibitory avoidance task and that these effects were blocked by adrenal medullectomy, lesions of the locus coeruleus, systemic or intra-basolateral amygdala ß-adrenergic receptor antagonism. Thus, the memory enhancing effects of ketamine anesthesia are time-dependent and mediated by a combined peripheral-central sympathomimetic action. We elucidated a mechanism by which ketamine exacerbates acute post-traumatic reaction, possibly leading to development of PTSD symptomatology later in life. These findings will help guide for a better management of sedation/anesthesia in emergency care to promote the prophylaxis and reduce the risk of developing trauma-related disorders in trauma victims.

Perinatal exposure to omega-3 fatty acid imbalance leads to early behavioral alterations in rat pups.

Polyunsaturated long-chain omega-3 fatty acids (n3-PUFAs) are crucially involved in brain development and function. Inadequate n3-PUFA intake in rats during the perinatal period leads to behavioral deficits in adulthood, but early behavioral changes have not yet been investigated. The present study aimed to investigate potential behavioral alterations in neonatal rats exposed to a perinatal n3-PUFA imbalance. Female Sprague Dawley rats were fed an n3-PUFA-enriched or an n3-PUFA-deficient diet throughout mating, pregnancy, and lactation. Controls were fed an n6/n3-PUFA-balanced diet. We observed maternal behavior from postnatal day (PND) 2 to PND 13 and tested pups in the isolation-induced ultrasonic vocalization (USV) emission task at PNDs 3, 5, 9 and 13 to evaluate the impact of perinatal n3-PUFA on early emotional traits. Both the n3-PUFA-enriched and n3-PUFA-deficient diets profoundly decreased maternal behavior. At PNDs 3 and PND 5, pups of the n3-PUFA-deficient or -enriched diet groups emitted significantly fewer USVs compared with control pups. Further, the sonographic pattern of the USVs was altered in the test pups compared with the control pups at PND 9 and PND 13. The present findings indicate that both n3-PUFA deficiency and supplementation induce alterations in mother-infant interaction and early behavioral disturbances in the offspring.

Effects of sevoflurane and clonidine on acid base status and long-term emotional and cognitive outcomes in spontaneously breathing rat pups.

BACKGROUND: Numerous experiments in rodents suggest a causative link between exposure to general anaesthetics during brain growth spurt and poor long-lasting neurological outcomes. Many of these studies have been questioned with regard of their translational value, mainly because of extremely long anaesthesia exposure. Therefore, the aim of the present study was to assess the impact of a short sevoflurane anaesthesia, alone or combined with clonidine treatment, on respiratory function in spontaneously breathing rat pups and overall effects on long-lasting emotional and cognitive functions. METHODS: At postnatal day (PND) 7, male Sprague Dawley rat pups were randomized into four groups and exposed to sevoflurane for one hour, to a single dose of intraperitoneal clonidine or to a combination of both and compared to a control group. Blood gas analysis was performed at the end of sevoflurane anaesthesia and after 60 minutes from clonidine or saline injection. Emotional and cognitive outcomes were evaluated in different group of animals at infancy (PND12), adolescence (PND 30-40) and adulthood (PND 70-90). RESULTS: Rat pups exposed to either sevoflurane or to a combination of sevoflurane and clonidine developed severe hypercapnic acidosis, but maintained normal arterial oxygenation. Emotional and cognitive outcomes were not found altered in any of the behavioural task used either at infancy, adolescence or adulthood. CONCLUSIONS: Sixty minutes of sevoflurane anaesthesia in newborn rats, either alone or combined with clonidine, caused severe hypercapnic acidosis in spontaneously breathing rat pups, but was devoid of long-term behavioural dysfunctions in the present setting.

Lifelong imbalanced LA/ALA intake impairs emotional and cognitive behavior via changes in brain endocannabinoid system.

Imbalanced dietary n-3 and n-6 PUFA content has been associated with a number of neurological conditions. Endocannabinoids are n-6 PUFA derivatives, whose brain concentrations are sensitive to modifications of fatty acid composition of the diet and play a central role in the regulation of mood and cognition. As such, the endocannabinoid system appears to be an ideal candidate for mediating the effects of dietary fatty acids on mood and cognition. Lifelong administration of isocaloric α-linolenic acid (ALA)-deficient and -enriched diets induced short-term memory deficits, whereas only dietary ALA enrichment altered emotional reactivity in adult male rats compared with animals fed a standard diet that was balanced in ALA/linoleic acid (LA) ratio. In the prefrontal cortex, both diets reduced 2-AG levels and increased MAG lipase expression, whereas only the enriched diet reduced AEA levels, simultaneously increasing FAAH expression. In the hippocampus, an ALA-enriched diet decreased AEA content and NAPE-PLD expression, and reduced 2-AG content while increasing MAG lipase expression. These findings highlight the importance of a diet balanced in fatty acid content for normal brain functions and to support a link between dietary ALA, the brain endocannabinoid system, and behavior, which indicates that dietary ALA intake is a sufficient condition for altering the endocannabinoid system in brain regions modulating mood and cognition.

Training-Associated Emotional Arousal Shapes Endocannabinoid Modulation of Spatial Memory Retrieval in Rats.

Variations in environmental aversiveness influence emotional memory processes in rats. We have previously shown that cannabinoid effects on memory are dependent on the stress level at the time of training as well as on the aversiveness of the environmental context. Here, we investigated whether the hippocampal endocannabinoid system modulates memory retrieval depending on the training-associated arousal level. Male adult Sprague Dawley rats were trained on a water maze spatial task at two different water temperatures (19°C and 25°C) to elicit either higher or lower stress levels, respectively. Rats trained under the higher stress condition had better memory and higher corticosterone concentrations than rats trained at the lower stress condition. The cannabinoid receptor agonist WIN55212-2 (10-30 ng/side), the 2-arachidonoyl glycerol (2-AG) hydrolysis inhibitor JZL184 (0.1-1 µg/side), and the anandamide (AEA) hydrolysis inhibitor URB597 (10-30 ng/side) were administered bilaterally into the hippocampus 60 min before probe-trial retention testing. WIN55212-2 or JZL184, but not URB597, impaired probe-trial performances only of rats trained at the higher stressful condition. Furthermore, rats trained under higher stress levels displayed an increase in hippocampal 2-AG, but not AEA, levels at the time of retention testing and a decreased affinity of the main 2-AG-degrading enzyme for its substrate. The present findings indicate that the endocannabinoid 2-AG in the hippocampus plays a key role in the selective regulation of spatial memory retrieval of stressful experience, shedding light on the neurobiological mechanisms involved in the impact of stress effects on memory processing. SIGNIFICANCE STATEMENT: Endogenous cannabinoids play a central role in the modulation of memory for emotional events. Here we demonstrate that the endocannabinoid 2-arachidonoylglycerol in the hippocampus, a brain region crucially involved in the regulation of memory processes, selectively modulates spatial memory recall of stressful experiences. Thus, our findings provide evidence that the endocannabinoid 2-arachidonoylglycerol is a key player in mediating the impact of stress on memory retrieval. These findings can pave the way to new potential therapeutic intervention for the treatment of neuropsychiatric disorders, such as post-traumatic stress disorder, where a previous exposure to traumatic events could alter the response to traumatic memory recall leading to mental illness.