The Influence of Early Life Interventions on Olfactory Memory Related to Palatable Food, and on Oxidative Stress Parameters and Na+/K+-ATPase Activity in the Hippocampus and Olfactory Bulb of Female Adult Rats

The effects of neonatal handling and the absence of ovarian hormones on the olfactory memory related to a palatable food in adulthood were investigated. Oxidative stress parameters and Na+/K+-ATPase activity in the hippocampus and olfactory bulb of adult pre-puberty ovariectomized female rats handled or not in the neonatal period were also evaluated. Litters were non-handled or handled (10 min/day, days 1-10 after birth). Females from each litter were divided into: OVX (subjected to ovariectomy), sham, and intact. When adults, olfactory memory related to a palatable food (chocolate) was evaluate using the hole-board olfactory task. Additionally, oxidative stress parameters and Na+/K+-ATPase activity were measured in the hippocampus and olfactory bulb. No difference between groups was observed considering olfactory memory evaluation. Neonatal handled rats presented an increase in Na+/K+-ATPase activity in the hippocampus and in the olfactory bulb, compared to non-handled ones. Considering the surgical procedure, there was a decrease in Na+/K+-ATPase and catalase activities in sham and OVX groups, compared to intact animals in the olfactory bulb. We concluded that olfactory memory related to a palatable food in adulthood was not affected by neonatal handling or by pre-puberty surgery, with or without removal of ovaries. The difference observed between groups in catalase and Na+/K+-ATPase activity does not seem to be related to the olfactory memory. Additionally, the increase in Na+/K+-ATPase activity (an enzyme that maintains the neurochemical gradient necessary for neuronal excitability) induced by neonatal handling may be related to neuroplastic changes in the hippocampus and olfactory bulb.     

Effect of neonatal handling and paternal care on offspring cognitive development in the monogamous California mouse (Peromyscus californicus)

In the laboratory rat and mouse, neonatal handling enhances hippocampal-dependent learning in adulthood, an effect mediated by changes in maternal behavior toward the handled young. In the present study, we examined the interaction between neonatal handling and biparental care during the early postnatal period and its effect on cognitive function in adult California mice (Peromyscus californicus). We characterized the parental behavior of handled and nonhandled father-present and father-absent families over the first 15 days of life. We then assessed cognitive performance of male and female offspring in the Barnes maze and object recognition test after they were 60 days of age. We found that the amount of licking and grooming received by pups was decreased in father-absent families. By postnatal days 12-15, licking and grooming in handled, father-absent families were equivalent to that of nonhandled, father-present families. Handling enhanced novel object recognition in father-present male mice with no effect in females. In the nonhandled group, the presence of the father had no effect on object recognition learning in male or female mice. Handling also enhanced spatial learning in the Barnes maze. In nonhandled families, the presence of the father appeared to have no effect on spatial learning in the male offspring. Interestingly, spatial learning in nonhandled, father-absent, female offspring was similar to that of handled animals. The average amount of licking and grooming received by pups was negatively correlated with the average number of errors made on the first day of reversal training in the Barnes maze. These data support previous findings that neonatal handling facilitates learning and memory in adulthood, suggest that under certain environmental conditions, there is a sex difference in the response of pups to paternal care, and further demonstrate the importance of active parental investment for offspring cognitive development.     

Neonatal Handling, Sweet Food Ingestion and Ectonucleotidase Activities in Nucleus Accumbens at Different Ages

Neonatal handled rats ingest more sweet food than non-handled ones, but it was documented only after puberty. Here, we studied the purinergic system in the nucleus accumbens, a possible target for the alteration in the preference for palatable food. We measured the ATP, ADP and AMP hydrolysis mediated by ectonucleotidases in synaptosomes of the nucleus accumbens in periadolescent and adult rats from different neonatal environments: non-handled and handled (10 min/day, first 10 days of life). Before adolescence, we found a decreased ingestion of sweet food in the neonatally handled group, with no effect on ATP, ADP or AMP hydrolysis. In adults, we found a greater ingestion of sweet food in the neonatally handled group, with no effect on ATPase or ADPase activities, but a decreased AMP hydrolysis. The nucleus accumbens is a site of intensive interaction between the adenosinergic and dopaminergic systems. Therefore, adenosine may modulate accumbens’ dopamine neurotransmission differently in neonatally handled rats.     

Early handling modulates outcome of neonatal dexamethasone exposure

Synthetic glucocorticoids such as dexamethasone (DEX) are used to prevent or treat respiratory disorders in prematurely born infants. Besides the short-term benefit on lung development, numerous human and animal studies have reported adverse neurodevelopmental side effects. In contrast, maternal care is known to exert a positive influence on neurodevelopmental outcome in rodents. The aim of the current study was therefore to investigate whether neonatal handling (days 1–21), known to induce maternal care, might serve as an intervention strategy modulating the adverse effects of DEX treatment (days 1–3). For this purpose we have measured the outcome of these early-life manipulations on development as well as adult endocrine and behavioral phenotype of male rats. Maternal care was observed during the first week of life and indeed enhanced in response to handling. Eye opening was accelerated and body weight reduced in DEX-treated animals. In adulthood, we report that handling ameliorated impaired spatial learning observed in DEX treated non-handled animals in the T-maze. Additionally, handling reduced susceptibility to the impact of DEX treatment in the water maze. Although DEX treatment and handling both resulted in enhanced negative feedback of the stress-induced corticosterone response and both reduced startle reactivity, the acquisition of fear was only reduced by handling, without effect of DEX. Interestingly, handling had a beneficial effect on pre-pulse inhibition, which was diminished after DEX treatment. In conclusion, these findings indicate that handling of the neonate enhances maternal care and attenuates specific DEX-induced alterations in the adult behavioral phenotype.     

Neonatal handling enhances contextual fear conditioning and alters corticosterone stress responses in young rats

Previous studies have indicated that neonatal handling influences development of hypothalamic-pituitary-adrenal (HPA) control of corticosterone. In addition, corticosterone influences memory consolidation processes in contextual fear conditioning. Therefore, neonatal handling may affect hippocampal-dependent memory processes present in contextual fear conditioning by influencing the development of HPA control of corticosterone. To investigate the effects of neonatal handling on early learning, rat pups were either handled (15-min removal from home cage) on the first 15 days after birth or left undisturbed in their home cage. Handled rats and nonhandled rats were fear conditioned at 18, 21, or 30 days of age and then tested at two time points--24 h following conditioning and at postnatal day 45. Subsequently, at approximately postnatal day 60, rats were exposed to restraint stress and corticosterone levels were assessed during restraint and recovery. Handled and nonhandled rats did not differ significantly in their freezing response immediately following footshock on the conditioning day. However, when tested for contextual fear conditioning at 24 h following conditioning and at postnatal day 45, handled rats showed more freezing behavior than nonhandled rats. When exposed to restraint stress, handled rats had a more rapid return of corticosterone to basal levels than nonhandled rats. These results indicate that neonatal handling enhances developmentally early memory processes involved in contextual fear conditioning and confirms previously reported effects of neonatal handling on HPA control of corticosterone.     

Enriched early experiences of mice underexpressing the beta-amyloid precursor protein restore spatial learning capabilities but not normal openfield behavior of adult animals

We have previously reported severely impaired spatial learning in mutant mice underexpressing a shortened variant of the beta-amyloid precursor protein (beta-APPtheta/theta). This targeted mutation is functionally equivalent to a null mutation. It also disturbs behavioral and neurological maturation with deficits emerging mainly between postnatal day (pd) 11 and 19. Such early tested mice exhibited almost no genotype-related difference in Morris water maze learning, raising the possibility that early handling might have compensated for genetic deficits. To verify this effect, we compared watermaze learning and open field behavior of 66 adult mutant and wildtype mice having been handled during pd 3-27 with that of 70 non-handled mutant and wildtype mice. Neurological testing during pd 3-27 markedly reduced time near wall and improved spatial retention of adult mutants, restoring their learning capabilities to wildtype levels. Early handling did not cure the mutation associated activity deficit in the open field, but mainly increased center field exploration in both mutants and wildtypes. In a follow-up experiment we analyzed whether an early (pd 3-10, n = 22) or middle (pd 11-19, n = 24) period of handling in form of neurological testing had differential effects on adult behavior. Mice handled during pd 11-19 had slightly shorter escape times than mice handled during pd 3-10 but were not significantly different in other behavioral measures. There were no sex related differences. Correlational and factor analysis showed that both the mutation and early handling had pleiotropic behavioral effects, resulting in differentially impaired mutants depending on the test situation. Likewise, early handling affected not only thigmotactic tendencies but also, more subtly, other behavioral components underlying water maze learning. We conclude that early postnatal stimulation can prevent mutation induced learning deficits in adult mice, but probably through other developmental mechanisms than those affected by the mutation. This implies that some behavioral impairments related to beta-APP malfunction may be corrected through simple treatments.     

Association Between Na<Superscript>+</Superscript>,K<Superscript>+</Superscript>-ATPase Activity and the Vulnerability/Resilience to Mood Disorders induced by Early Life Experience

There is increasing evidence that early life events can influence neurodevelopment and later susceptibility to disease. Chronic variable stress (CVS) has been used as a model of depression. The objective of this study was to evaluate the interaction between early experience and vulnerability to chronic variable stress in adulthood, analyzing emotional, metabolic and neurochemical aspects related to depression. Pups were (1) handled (10 min/day) or (2) left undisturbed from day 1 to 10 after birth. When the animals reached adulthood, the groups were subdivided and the rats were submitted or not to CVS, which consisted of daily exposure to different stressors for 40 days, followed by a period of behavioral tasks, biochemical (plasma corticosterone and insulin sensitivity) and neurochemical (Na⁺,K⁺-ATPase activity in hippocampus, amygdala and parietal cortex) measurements. Neonatally-handled rats demonstrated shorter immobility times in the forced swimming test, independently of the stress condition. There was no difference concerning basal corticosterone or insulin sensitivity between the groups. Na⁺,K⁺-ATPase activity was decreased in hippocampus and increased in the amygdala of neonatally-handled rats. CVS decreased the enzyme activity in the three structures, mainly in the non-handled group. These findings suggest that early handling increases the ability to cope with chronic variable stress in adulthood, with animals showing less susceptibility to neurochemical features associated with depression, confirming the relevance of the precocious environment to vulnerability to psychiatric conditions in adulthood.     

Effects of neonatal handling on social memory, social interaction, and number of oxytocin and vasopressin neurons in rats

Early-life environmental events can induce profound long-lasting changes in several behavioral and neuroendocrine systems. The neonatal handling procedure, which involves repeated brief maternal separations followed by experimental manipulations, reduces stress responses and sexual behavior in adult rats. The purpose of this study was to analyze the effects of neonatal handling on social behaviors of male and female rats in adulthood, as manifest by the results of social memory and social interaction tests. The number of oxytocin (OT) and vasopressin (VP) neurons in the paraventricular (PVN) and supraoptic (SON) nuclei of hypothalamus were also analyzed. The results did not demonstrate impairment of social memory. Notwithstanding, handling did reduce social investigative interaction and increase aggressive behavior in males, but did not do so in females. Furthermore, in both males and females, handling was linked with reduced number of OT-neurons in the parvocellular region of the PVN, while no differences were detected in the magnocellular PVN or the SON. On the other hand, handled males exhibited increased number of VP-neurons in the magnocellular zone of the PVN. We may conclude that the repeated brief maternal separations can reduce affiliative social behavior in adult male rats. Moreover, the disruption of the mother-infant relationship caused by the handling procedure induced long-lasting morphological changes in critical neuroendocrine areas that are involved in social bonding in mammals.     

Inhibition of DNA Methylation in the Developing Rat Brain Disrupts Sexually Dimorphic Neurobehavioral Phenotypes in Adulthood

Accumulating evidence indicates a critical implication of DNA methylation in the brain development. We aim to determine whether the disruption of DNA methylation patterns in the developing brain adversely affects neurobehavioral phenotypes later in life in a sex-dependent manner. 5-Aza-2′-deoxycytidine (5-Aza), a DNA methylation inhibitor, was administered in newborn rats from postnatal day 1 to 3. Neurobehavioral outcomes were analyzed at 3 months of age. 5-Aza treatment significantly inhibited DNA methyltransferase activity and decreased global DNA methylation levels in neonatal rat brains, resulting in asymmetric growth restriction with the increased brain to body weight ratio in both male and female rats at 14 days and 3 months of age. Compared with the saline control, 5-Aza treatment significantly improved performance of male rats on the rotarod test, and 5-Aza-treated female rats demonstrated less anxiety, less depression-like behaviors, and enhanced spatial learning performance. Of importance, neonatal 5-Aza treatment eliminated the sexually dimorphic differences in several neurobehavioral tests in adult rats. In addition, 5-Aza treatment decreased promoter methylation of brain-derived neurotrophic factor (BDNF) gene and significantly increased BDNF mRNA and protein abundance in the prefrontal cortex and hippocampus of female rats in a sex-dependent manner. Thus, brain DNA methylation appears to be essential for sexual differentiations of the brain and neurobehavioral functions. Inhibition of DNA methylation in the developing brain of early life induces aberrant neurobehavioral profiles and disrupts sexually dimorphic neurobehavioral phenotypes in adulthood, of which altered BDNF signaling pathway may be an important mediator.     

Escape versus exploratory activity: An interpretation of rats' behaviour in the open field and a light-dark preference test

To test the assumption that dark preference in rats can serve as a measure of emotionality, dark preference was compared with ambulation and defacation in the open field. One group of 80-days-old male rats was handled for seven days; another group remained undisturbed. All animals were tested on each of five successive days in both a light-dark preference situation and an open field. Handled rats ambulated more in the field and stayed less time in the dark than non-handled ones. Significant negative correlations were found for the different days between open field ambulation and dark preference. Correlations between dark preference and open field defacation were positive except on day one. From the first to the second trial dark preference increased in both groups while open field ambulation decreased. The results were considered to support the hypothesis of dark preference as a measure of emotionality.In a second study an investigation was made as to whether high initial activity in a new situation is brought about by exploration or by an escape tendency. Again one group of male albino rats was handled. During testing, half of the handled and half of the non-handled rats had the chance of escaping from the open field into the adjacent home cage. From there the animals had the possibility of re-entering the field. The second half of each group had to stay in the field. These latter animals showed a remarkable decrease in ambulation from the first to the second trial. Rats which had access to their home cages seldom re-entered the field in the first trial. In later trials, however, ambulation in the field increased. Non-handled rats needed more trials before they started investigating the field. It was concluded that this result gives more support to an explanation of initial activity in terms of escape behaviour.     

Differential outcomes of unilateral interferences at birth

Behavioural modifications, including modifications of emotional reactivity, can occur following early experience such as handling (manual rubbing). Here, we investigated the effects of unilateral tactile stimulation at an early stage on emotional reactions later on. We handled newborn foals intensively on one side of their body. This early unilateral tactile experience had medium-term effects: the reactions of foals to a human approach, when they were 10 days old, differed according to the side stimulated at birth. Fewer right-handled foals accepted contact with humans, they delayed first contact longer and they evaded approaching humans sooner than did non-handled and left-handled foals. These results raise questions concerning the organization of neonatal care in animals and humans.     

Neonatal inhalatory anesthetic exposure: reproductive changes in male rats

We investigated the effects of an inhalatory anesthetic (ethyl ether) during the neonatal period of brain sexual differentiation on the later fertility and sexual behavior of male rats. Animals were exposed to ethyl ether immediately after birth. At adulthood, body weight, testes wet weight, and plasma testosterone levels were not affected; however, neonatal exposure to ether showed alterations on male fertility: a decrease in the number of spermatids and spermatozoa, an increase in the transit time of cauda epididymal spermatozoa and a decrease in daily sperm production. An alteration of sexual behavior was also observed: decreased male sexual behavior and appearance of homosexual behavior when the male rats were castrated and pretreated with exogenous estrogen. Probably, the ether delayed or reduced the testosterone peak of the sexual differentiation period, altering the processes of masculinization and defeminization of the hypothalamus. Our results indicate that perinatal exposure to ethyl ether during the critical period of male brain sexual differentiation, acting as endocrine disruptors, has a long-term effect on the fertility and sexual behavior of male rats, suggesting endocrine disruption through incomplete masculinization and defeminization of the central nervous system.     

Long-Lasting Effects of Maternal Separation on an Animal Model of Post-Traumatic Stress Disorder: Effects on Memory and Hippocampal Oxidative Stress

Adverse early life events, such as periodic maternal separation, may alter the normal pattern of brain development and subsequently the vulnerability to a variety of mental disorders in adulthood. Patients with a history of early adversities show higher frequency of post-traumatic stress disorder (PTSD). This study was undertaken to verify if repeated long-term separation of pups from dams would affect memory and oxidative stress parameters after exposure to an animal model of PTSD. Nests of Wistar rats were divided into intact and subjected to maternal separation (incubator at 32°C, 3 h/day) during post-natal days 1–10. When adults, the animals were subdivided into exposed or not to a PTSD model consisting of exposure to inescapable footshock, followed by situational reminders. One month after exposure to the shock, the animals were exposed to a memory task (Morris water maze) and another month later animals were sacrificed and DNA breaks and antioxidant enzymes activities were measured in the hippocampus. Rats exposed to shock or maternal separation plus shock showed long-lasting effects on spatial memory, spending more time in the opposite quadrant of the water maze. This effect was higher in animals subjected to both maternal separation and shock. Both shock and maternal separation induced a higher score of DNA breaks in the hippocampus. No differences were observed on antioxidant enzymes activities. In conclusion, periodic maternal separation may increase the susceptibility to the effects of a stressor applied in adulthood on performance in the water maze. Increased DNA breaks in hippocampus was induced by both, maternal separation and exposure to shock.     

Liver enzyme adaptation after lithium administration in handled and nonhandled rats.

We have examined the interaction of lithium administration and the infant stimulation procedure of handling on hormonally regulated enzymes of liver. Animals handled in infancy show an increased morning corticosterone level in response to lithium feeding and markedly elevated serum glucose during refeeding following a two day fast, when compared to non-handled control animals. Lithium alters serum corticosterone both in response to the stress of fasting, and during the diurnal cycle following glucose refeeding. The handled and non-handled animals respond differently. These results are consistent with previously reported alterations in feedback regulation of ACTH secretion in handled animals. They also indicate a further modification of this system in response to lithium administration.     

Neonatal handling increases sensitivity to acute neurodegeneration in adult rats

Environmental stimuli during the perinatal period can result in persistent individual differences in neural viability and cognitive functions. Earlier studies have shown that brief daily maternal separation and/or handling of rat pups during the first weeks of life reduces stress reactivity during adulthood and attenuates neuronal loss and cognitive decline during aging. In the present study we examined whether neonatal handling also affects the sensitivity of the adult brain to an acute neurotoxic insult. Postnatally handled and nonhandled control rats were left undisturbed from weaning onwards until the age of 11 months. At this age, the animals were subjected to a neurotoxic challenge by unilateral infusion of 60 mM of the glutamate analogue N-methyl-D-aspartate (NMDA) into the nucleus basalis magnocellularis (NBM). The brains were collected to measure cholinergic cell and fiber loss. In the nonlesioned side of the brain, cholinergic cell number in the NBM and fiber density in the cortex were not different between postnatally handled and control rats. However, in the lesioned hemisphere handled animals exhibited a significantly higher loss of choline-acetyltransferase-immunoreactive and acetylcholinesterase-positive fibers in the somatosensory cortex. The present results provide evidence for an enhanced vulnerability of postnatally handled rats to acute neurodegeneration in contrast to the previously reported attenuation of spontaneous aging-related neurodegenerative processes.     

Influence of prenatal stress on the rat hypothalamic-pituitary-adrenal axis activity: the role of the brain glycocorticoid receptors

The effects of prenatal stress on the hypothalamic-pituitary-adrenal (HPA) axis activity and brain glycocorticoid receptors were studied in neonatal male and female offspring, as well as the influence of neonatal glycocorticoid receptors blockade on hormonal stress reactivity of adult rats. The results showed that there were sexual differences in plasma corticosterone level and corticosteroid binding in the cortex and hypothalamus of 5-day old control rats. Prenatal stress increased basal level of corticosterone in female rats, decreased corticosterone binding in hypothalamus and hippocampus of male and female rats, and increased corticosteroid receptor level in the male cortex. Neonatal administration of glycocorticoid receptor antagonist did not change plasma corticosterone level in 5-day old rats, but prolonged hormonal stress response of the HPA axis in adult male rats and increased hormonal stress response in female ones. The character of the IIPA axis activity of male and female rats with neonatal blockade of glycocorticoid receptors correspond to hormonal stress response of prenatal stressed rats. These data suggest that change of brain glycocorticoid receptors function in neonatal period of development might be one of the mechanisms of prenatal stress influence on the HPA axis activity in the adulthood.     

Effects of early undernutrition and handling on the adrenocortical activity of neonatal rats

Early neonatal experiences such as handling or undernutrition may alter developmental patterns associated with brain maturation and neuroendocrine regulation. Therefore, we tested neonatal ACTH and corticosterone responses to ether stress in pups submitted to chronic underfeeding which involves daily handling (U), daily handling only (H), or no handling (I). Pituitary ACTH content and brain myelin basic protein (MBP) content were measured in all rat groups. We found that the order of magnitude in stress-induced ACTH secretion was: I greater than H greater than U on day 14 and 18 of age while on day 10, only a small significant response in the H group was observed. Corticosterone secretion after stress was increased on day 14 in both H and I rats while no response was observed in the U group at all ages. Pituitary ACTH content of U pups was significantly (p less than 0.01) reduced compared to H rats on day 10 of age but not later. Underfeeding had profound effects on MBP synthesis of U rats since brain MBP content on day 14 was 5-fold lower in U versus H pups. In addition, handling enhanced MBP production since H rats exhibited higher (p less than 0.05) MBP content as compared to I rats. Thus, both handling and undernutrition experienced early in life are able to affect central brain maturation as well as neonatal adrenocortical responses to stress.     

Effects of genistein in the maternal diet on reproductive development and spatial learning in male rats

Endocrine disruptors, chemicals that disturb the actions of endogenous hormones, have been implicated in birth defects associated with hormone-dependent development. Phytoestrogens are a class of endocrine disruptors found in plants. In the current study we examined the effects of exposure at various perinatal time periods to genistein, a soy phytoestrogen, on reproductive development and learning in male rats. Dams were fed genistein-containing (5 mg/kg feed) food during both gestation and lactation, during gestation only, during lactation only, or during neither period. Measures of reproductive development and body mass were taken in the male offspring during postnatal development, and learning and memory performance was assessed in adulthood. Genistein exposure via the maternal diet decreased body mass in the male offspring of dams fed genistein during both gestation and lactation, during lactation only, but not during gestation only. Genistein decreased anogenital distance when exposure was during both gestation and lactation, but there was no effect when exposure was limited to one of these time periods. Similarly, spatial learning in the Morris water maze was impaired in male rats exposed to genistein during both gestation and lactation, but not in rats exposed during only one of these time periods. There was no effect of genistein on cued or contextual fear conditioning. In summary, the data indicate that exposure to genistein through the maternal diet significantly impacts growth in male offspring if exposure is during lactation. The effects of genistein on reproductive development and spatial learning required exposure throughout the pre- and postnatal periods.     

Gender and estrous cycle influences on behavioral and neurochemical alterations in adult rats neonatally administered ketamine

Neonatal N‐methyl‐D‐aspartate (NMDA) receptor blockade in rodents triggers schizophrenia (SCZ)‐like alterations during adult life. SCZ is influenced by gender in age of onset, premorbid functioning, and course. Estrogen, the hormone potentially driving the gender differences in SCZ, is known to present neuroprotective effects such as regulate oxidative pathways and the expression of brain‐derived neurotrophic factor (BDNF). Thus, the aim of this study was to verify if differences in gender and/or estrous cycle phase during adulthood would influence the development of behavioral and neurochemical alterations in animals neonatally administered ketamine. The results showed that ketamine‐treated male (KT‐male) and female‐in‐diestrus (KTF‐diestrus, the low estrogen phase) presented significant deficits in prepulse inhibition of the startle reflex and spatial working memory, two behavioral SCZ endophenotypes. On the contrary, female ketamine‐treated rats during proestrus (KTF‐proestrus, the high estradiol phase) had no behavioral alterations. This correlated with an oxidative imbalance in the hippocampus (HC) of both male and KTF‐diestrus female rats, that is, decreased levels of GSH and increased levels of lipid peroxidation and nitrite. Similarly, BDNF was decreased in the KTF‐diestrus rats while no alterations were observed in KTF‐proestrus and male animals. The changes in the HC were in contrast to those in the prefrontal cortex in which only increased levels of nitrite in all groups studied were observed. Thus, there is a gender difference in the adult rat HC in response to ketamine neonatal administration, which is based on the estrous cycle. This is discussed in relation to neuropsychiatric conditions and in particular SCZ. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 519–532, 2016     

Neonatal exposure of ketamine inhibited the induction of hippocampal long-term potentiation without impairing the spatial memory of adult rats

Ketamine is one of general anesthetics and has been commonly used in obstetric and pediatric anesthesia. However, effects of exposure to ketamine on neonatal brain are largely unknown. In this study, we aim to investigate the effect of neonatal exposure of ketamine on spatial memory and long-term potentiation (LTP) in the hippocampus of adult rats. One-week-old neonatal rats were separated into ketamine group and control group. Neonatal rats in ketamine group were received intraperitoneal injection of 25 mg/kg (low-dose group, N = 8) or 50 mg/kg ketamine (high-dose group, N = 8). Neonatal Rats in control group received saline injection (N = 8). After 10 weeks, the spatial memory of adult rats was examined by using Morris Water Maze, and LTP in the hippocampus of adult rats was assessed by electrophysiological experiment. We found that exposure of ketamine to neonatal rats, either low-dose or high-dose, had not induced alteration on their adulthood’s escape latency, swimming speed and the percentage of time spent in original quadrant compared with the control. The electrophysiological examination showed that the induction of LTP in hippocampus was significantly reduced in adult rats of ketamine group (either low-dose or high-dose). Our study showed that neonatal exposure of ketamine inhibited the induction of hippocampal LTP without impairing the spatial memory of adult rats.