(In)Equality and Beyond: Achieving Justice in Gender-Affirming Hormone Initiation.

ABSTRACT: The World Professional Association for Transgender Health (WPATH) is an international organization that aims to advocate for transgender and gender-diverse (TGD) people by promoting safe and effective ways to access and deliver healthcare to maximize psychological health and well-being. One way this is achieved is through the WPATH's published Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People, a set of guidelines for gender-affirming care that is based on the available science and expert consensus. In anticipation of the release of updated guidelines (Standards of Care Version 8) in 2022 the Radcliffe Institute for Advanced Study at Harvard University hosted an Exploratory Seminar in December 2021 that brought together experts from the United States, Mexico, and the United Kingdom to share knowledge across disciplines in order to propose revisions to the WPATH's updated guidelines. This article shares the workgroup's high-level consensus and recommendations.

Maternal deprivation impairs memory and cognitive flexibility, effect that is avoided by environmental enrichment.

Maternal deprivation (MD) causes cognitive deficits that persist until adulthood. Thereby, the environmental enrichment (EE) is widely used to increase brain plasticity. Here, pregnant female rats were used and their offspring were submitted to neonatal MD from post-natal day 1-10; after weaning the rats were submitted to EE. MD caused deficits on short and long-term aversive and recognition memory and on cognitive flexibility tested on reversed Morris Water Maze test. MD also promoted the decrease of hippocampal Brain-Derived Neurotropic Factor (BDNF) protein expression. The EE was able to protect against the cognitive deficits, avoiding the memory and the cognitive flexibility disrupting, and normalizing hippocampal BDNF expression of rats submitted to MD. These data confirms that MD promotes long-life memory deficits and demonstrates that MD causes cognitive flexibility disruption; the mechanisms seem involve the decrease of BDNF. We also demonstrate that EE, which improves BDNF, is able to avoid memory deficits and cognitive flexibility disrupts.

How Early Life Stress Impact Maternal Care: A Systematic Review of Rodent Studies.

Background: Maternal care refers to the behavior performed by the dam to nourish and protect her litter during its early development. Frequent and high-quality performance of such maternal behaviors is critical for the neurodevelopment of the pups. Maternal exposure to stress during early development can impair maternal care and amplify the deleterious effects of poor maternal caregiving and neglect. As such, a thorough understanding of the effects caused by several models of early life stress on maternal care may yield more insights into the relationship between stress and maternal behavior. Methods: A systematic review was performed to identify and address the effects of early life stress on maternal behavior. The search was conducted using three online databases: PUBMED, Embase, and Web of Science. To provide clear evidence of the impact of stress on maternal care, in every study, the stress group was always compared to a control group. Outcomes were categorized into eight different behaviors: (1) licking/grooming; (2) arched-back nursing; (3) blanket-nursing/passive nursing; (4) nest building; (5) contact with pups; (6) harmful/adverse caregiving; (7) no contact; (8) nest exits. Additionally, the methodological quality of the studies was evaluated. Results: A total of 12 different early life stress protocols were identified from the 56 studies included in this systematic review. Our data demonstrate that different stress models can promote specific maternal patterns of behavior. Regarding the maternal separation protocol, we observed an overall increase in nursing and licking/grooming behaviors, which are essential for pup development. An increase in the number of nest exits, which represents a fragmentation of maternal care, was observed in the limited bedding protocol, but the total amount of maternal care appears to remain similar between groups. Conclusions: Each stress protocol has unique characteristics that increase the difficulty of rendering comparisons of maternal behavior. The increase in maternal care observed in the maternal separation protocol may be an attempt to overcompensate for the time off-nest. Fragmented maternal care is a key component of the limited bedding protocol. Moreover, the methodological approaches to evaluate maternal behavior, such as time, duration, and behavior type should be more homogeneous across studies.

Repeated three-hour maternal deprivation as a model of early-life stress alters maternal behavior, olfactory learning and neural development.

Early life stress such as physical abuse, trauma or neglect during a critical period of development can elicit negative long-lasting effects on health. Neonatal maternal deprivation (MD) is a stressful event capable of triggering structural and neurobiological changes in Central Nervous System (CNS) development during proliferative and migratory cell differentiation. In this study, we investigated the maternal behavior of lactating rats submitted to protocol of chronic neonatal maternal deprivation (MD) during postnatal day (PND) 1 until 10. We analyzed the effects of the MD in the olfactory memory and cellular proliferation and differentiation in the hippocampus and olfactory bulb in Wistar rat pups on 7, 11 and 21 days postpartum. Analysis in active neurons, cellular differentiation and proliferation, were marked and evaluated by flow cytometry in tissue samples of hippocampi and olfactory bulb. Our results demonstrated an increase in maternal behavior immediately after dam's return to the home-cage in MD group compared to the non-deprived group. In addition, MD pups spent more time (higher latency) to identify the nest odor in comparison to the non-deprived rat pups in the olfactory learning task and showed a significant delay in the neural differentiation and proliferation in the hippocampus and olfactory bulb. These results reveal that disruptions in the mother-infant bonding by the MD induce changes in maternal behavior and interaction with the offspring that could be leading to delayed CNS development and significant impairment in offspring's olfactory learning.

Maternal behavior of the mouse dam toward pups: implications for maternal separation model of early life stress.

Maternal care is essential for an adequate pup development, as well as for the health of the dam. Exposure to stress in early stages of life can disrupt this dam-pup relationship promoting altered neurobiological and behavioral phenotypes. However, there is a lack of consensus regarding the effects of daily maternal separation (MS) on the pattern of maternal behavior. The aim of this study is to compare the patterns of maternal behavior between mice exposed to MS and controls. BALB/c mice were subjected to MS for a period of 180 min/day from postnatal day 2-7 (n = 17) or designated to be standard animal facility reared (AFR) controls (n = 19). Maternal behaviors were computed as frequency of nursing, licking pups and contact with pups, and nonmaternal behaviors were computed as frequency of actions without interaction with pups and eating/drinking. A total of 18 daily observations of maternal behavior were conducted during these six days, and considering the proportion of maternal and nonmaternal behaviors, an index was calculated. There was no difference when comparing the global index of maternal behavior between the AFR and MS animals by the end of the observed period. However, the pattern of maternal behavior between groups was significantly different. While MS dams presented low frequency of maternal behavior within the first couple days of the stress protocol, but increasing over time, AFR dams showed higher maternal behavior at the beginning, reducing over time. Together, our results indicate that MS alters the maternal behavior of the dams toward pups throughout the first week of the stress protocol and provoked some anxiety-related traits in the dams. The inversion of maternal behavior pattern could possibly be an attempt to compensate the low levels of maternal care observed in the first days of MS.

Histamine regulates memory consolidation.

Recent findings have reasserted the role of histamine in the regulation of memory consolidation first proposed in 1986 in an inhibitory avoidance task in rats. They indicate that histamine is indeed a major regulator of memory consolidation in various tasks, through H2 receptors in the dorsal hippocampus and through H3 receptors in the basolateral amygdala, depending on the task. In the object recognition task, the memory enhancing effect is mediated by the three receptors (H1, H2, H3) in the dorsal hippocampus. In social recognition, the consolidation effect is mediated by H2 receptors in both amygdala and dorsal hippocampus. Data have suggested, in addition, influences on retrieval; this has been best studied in the dorsal hippocampus in step-down inhibitory avoidance task. Depending on the recent history of the conditioned stimulus (i.e., whether it has been recently reinforced or not), histamine acts on hippocampal H1 receptors, facilitating retrieval, or on H2 receptors, inhibiting it.

Histamine in the basolateral amygdala promotes inhibitory avoidance learning independently of hippocampus.

Recent discoveries demonstrated that recruitment of alternative brain circuits permits compensation of memory impairments following damage to brain regions specialized in integrating and/or storing specific memories, including both dorsal hippocampus and basolateral amygdala (BLA). Here, we first report that the integrity of the brain histaminergic system is necessary for long-term, but not for short-term memory of step-down inhibitory avoidance (IA). Second, we found that phosphorylation of cyclic adenosine monophosphate (cAMP) responsive-element-binding protein, a crucial mediator in long-term memory formation, correlated anatomically and temporally with histamine-induced memory retrieval, showing the active involvement of histamine function in CA1 and BLA in different phases of memory consolidation. Third, we found that exogenous application of histamine in either hippocampal CA1 or BLA of brain histamine-depleted rats, hence amnesic, restored long-term memory; however, the time frame of memory rescue was different for the two brain structures, short lived (immediately posttraining) for BLA, long lasting (up to 6 h) for the CA1. Moreover, long-term memory was formed immediately after training restoring of histamine transmission only in the BLA. These findings reveal the essential role of histaminergic neurotransmission to provide the brain with the plasticity necessary to ensure memorization of emotionally salient events, through recruitment of alternative circuits. Hence, our findings indicate that the histaminergic system comprises parallel, coordinated pathways that provide compensatory plasticity when one brain structure is compromised.

Brain Histamine Is Crucial for Selective Serotonin Reuptake Inhibitors' Behavioral and Neurochemical Effects.

BACKGROUND: The neurobiological changes underlying depression resistant to treatments remain poorly understood, and failure to respond to selective serotonin reuptake inhibitors may result from abnormalities of neurotransmitter systems that excite serotonergic neurons, such as histamine. METHODS: Using behavioral (tail suspension test) and neurochemical (in vivo microdialysis, Western-blot analysis) approaches, here we report that antidepressant responses to selective serotonin reuptake inhibitors (citalopram or paroxetine) are abolished in mice unable to synthesize histamine due to either targeted disruption of histidine decarboxylase gene (HDC(-/-)) or injection of alpha-fluoromethylhistidine, a suicide inhibitor of this enzyme. RESULTS: In the tail suspension test, all classes of antidepressants tested reduced the immobility time of controls. Systemic reboxetine or imipramine reduced the immobility time of histamine-deprived mice as well, whereas selective serotonin reuptake inhibitors did not even though their serotonergic system is functional. In in vivo microdialysis experiments, citalopram significantly increased histamine extraneuronal levels in the cortex of freely moving mice, and methysergide, a serotonin 5-HT1/5-HT2 receptor antagonist, abolished this effect, thus suggesting the involvement of endogenous serotonin. CREB phosphorylation, which is implicated in the molecular mechanisms of antidepressant treatment, was abolished in histamine-deficient mice treated with citalopram. The CREB pathway is not impaired in HDC(-/-) mice, as administration of 8-bromoadenosine 3', 5'-cyclic monophosphate increased CREB phosphorylation, and in the tail suspension test it significantly reduced the time spent immobile by mice of both genotypes. CONCLUSIONS: Our results demonstrate that selective serotonin reuptake inhibitors selectively require the integrity of the brain histamine system to exert their preclinical responses.

Histamine acting on the basolateral amygdala reverts the impairment of aversive memory of rats submitted to neonatal maternal deprivation.

Recent findings suggest a role of brain histamine in the regulation of memory consolidation, particularly in one-trial inhibitory avoidance (IA) learning and that disruption in the mother infant relationship i.e. maternal deprivation induces cognitive deficits. We investigate whether histamine itself, and histaminergic compounds given into the basolateral amygdala (BLA) immediately post-training can affect retention (24 h after training) of one-trial (IA) in rats submitted to early postnatal maternal deprivation. In all cases, deprived (Dep) animals had lower retention scores than non-deprived controls (N-dep). Histamine induced memory enhancement on its own in N-dep animals and was able to overcome the deleterious effect of Dep. The effects by SKF-91488 is similar to histamine. The H3 agonist, imetit mimetized the enhancing effects of histamine; neither agonist H1 pyridylethylamine nor the H2 dimaprit had any effect. Ranitidine and thioperamide (50 nmol) co-infused with histamine (10 nmol) fully blocked the restorative effect of histamine on retention in Dep animals. Thioperamide, in addition, blocked the enhancing effect of histamine on memory of the N-dep animals as well. None of the drugs used given into BLA had any effect on open-field or elevated plus-maze behavior in N-dep or Dep rats. Our results are limited to experimental design in rats. Extrapolation i.e. in humans requires further experimentations. The present results suggest that the memory deficit induced by early postnatal maternal deprivation in rats may at least in part be due to an impairment of histamine H3 receptor-mediated mediated mechanisms in the BLA.

Hippocampal molecular mechanisms involved in the enhancement of fear extinction caused by exposure to novelty.

Exposure to a novel environment enhances the extinction of contextual fear. This has been explained by tagging of the hippocampal synapses used in extinction, followed by capture of proteins from the synapses that process novelty. The effect is blocked by the inhibition of hippocampal protein synthesis following the novelty or the extinction. Here, we show that it can also be blocked by the postextinction or postnovelty intrahippocampal infusion of the NMDA receptor antagonist 2-amino-5-phosphono pentanoic acid; the inhibitor of calcium/calmodulin-dependent protein kinase II (CaMKII), autocamtide-2-related inhibitory peptide; or the blocker of L-voltage-dependent calcium channels (L-VDCCs), nifedipine. Inhibition of proteasomal protein degradation by ß-lactacystin has no effect of its own on extinction or on the influence of novelty thereon but blocks the inhibitory effects of all the other substances except that of rapamycin on extinction, suggesting that their action depends on concomitant synaptic protein turnover. Thus, the tagging-and-capture mechanism through which novelty enhances fear extinction involves more molecular processes than hitherto thought: NMDA receptors, L-VDCCs, CaMKII, and synaptic protein turnover.

New frontiers in the study of memory mechanisms.

We review recent work on three major lines of memory research: a) the possible role of the protein kinase M-zeta (PKMzeta) in memory persistence; b) the processes of "synaptic tagging and capture" in memory formation; c) the modulation of extinction learning, widely used in the psychotherapy of fear memories under the name of "exposure therapy". PKMzeta is a form of protein kinase C (PKC) that apparently remains stimulated for months after the consolidation of a given memory. Synaptic tagging is a mechanism whereby the weak activation of one synapse can tag it with a protein so other synapses in the same cell can reactivate it by producing other proteins that bind to the tag. Extinction, once mistakenly labeled as a form of forgetting, is by itself a form of learning; through it animals can learn to inhibit a response. We now know it can be modulated by neurotransmitters or by synaptic tagging, which should enable better control of its clinical use.

The role of histamine receptors in the consolidation of object recognition memory.

Findings have shown that histamine receptors in the hippocampus modulate the acquisition and extinction of fear motivated learning. In order to determine the role of hippocampal histaminergic receptors on recognition memory, adult male Wistar rats with indwelling infusion cannulae stereotaxically placed in the CA1 region of dorsal hippocampus were trained in an object recognition learning task involving exposure to two different stimulus objects in an enclosed environment. In the test session, one of the objects presented during training was replaced by a novel one. Recognition memory retention was assessed 24 h after training by comparing the time spent in exploration (sniffing and touching) of the known object with that of the novel one. When infused in the CA1 region immediately, 30, 120 or 360 min posttraining, the H1-receptor antagonist, pyrilamine, the H2-receptor antagonist, ranitidine, and the H3-receptor agonist, imetit, blocked long-term memory retention in a time dependent manner (30-120 min) without affecting general exploratory behavior, anxiety state or hippocampal function. Our data indicate that histaminergic system modulates consolidation of object recognition memory through H1, H2 and H3 receptors.

Memory reconsolidation and its maintenance depend on L-voltage-dependent calcium channels and CaMKII functions regulating protein turnover in the hippocampus.

Immediate postretrieval bilateral blockade of long-acting voltage-dependent calcium channels (L-VDCCs), but not of glutamatergic NMDA receptors, in the dorsal CA1 region of the hippocampus hinders retention of long-term spatial memory in the Morris water maze. Immediate postretrieval bilateral inhibition of calcium/calmodulin-dependent protein kinase (CaMK) II in dorsal CA1 does not affect retention of this task 24 h later but does hinder it 5 d later. These two distinct amnesic effects are abolished if protein degradation by proteasomes is inhibited concomitantly. These results indicate that spatial memory reconsolidation depends on the functionality of L-VDCC in dorsal CA1, that maintenance of subsequent reconsolidated memory trace depends on CaMKII, and these results also suggest that the role played by both L-VDCC and CaMKII is to promote the retrieval-dependent, synaptically localized enhancement of protein synthesis necessary to counteract a retrieval-dependent, synaptic-localized enhancement of protein degradation, which has been described as underlying the characteristic labilization of the memory trace triggered by retrieval. Thus, conceivably, L-VDCC and CaMKII would enhance activity-dependent localized protein renewal, which may account for the improvement of the long-term efficiency of the synapses responsible for the maintenance of reactivated long-term spatial memory.

New frontiers in the study of memory mechanisms

We review recent work on three major lines of memory research: a) the possible role of the protein kinase M-zeta (PKMzeta) in memory persistence; b) the processes of “synaptic tagging and capture” in memory formation; c) the modulation of extinction learning, widely used in the psychotherapy of fear memories under the name of “exposure therapy”. PKMzeta is a form of protein kinase C (PKC) that apparently remains stimulated for months after the consolidation of a given memory. Synaptic tagging is a mechanism whereby the weak activation of one synapse can tag it with a protein so other synapses in the same cell can reactivate it by producing other proteins that bind to the tag. Extinction, once mistakenly labeled as a form of forgetting, is by itself a form of learning; through it animals can learn to inhibit a response. We now know it can be modulated by neurotransmitters or by synaptic tagging, which should enable better control of its clinical use.

Histamine infused into basolateral amygdala enhances memory consolidation of inhibitory avoidance.

The role of the basolateral amygdala (BLA) in the consolidation of aversive memory is well established. Here we investigate the involvement of the histaminergic system in BLA on this variable. Rats were chronically implanted with bilateral cannulae in the BLA and after recovery were trained in a one-trial step-down inhibitory avoidance task. Immediately after training histaminergic compounds either alone or in combination were infused through the cannulae. Memory was assessed in test sessions carried out 24 h after the training session. Post-training histamine (1-10 nmol; 0.5 µl/side) enhanced consolidation and the histamine H3 receptor antagonist thioperamide (50 nmol; 0.5 µl/side) impaired memory consolidation. The effect was shared by the histamine N-methyltransferase inhibitor SKF-91844 (50 nmol; 0.5 µl/side) as well as by the H3 receptor agonist imetit (10 nmol; 0.5 µl/side). The promnesic action of histamine was unaffected by the H1 receptor antagonist pyrilamine (50 nmol; 0.5 µl/side). The H1 receptor agonist pyridylethylamine (10 nmol; 0.5 µl/side), the H2 agonist dimaprit (10 nmol; 0.5 µl/side) and the H2 antagonist ranitidine (50 nmol; 0.5 µl/side) were ineffective. Histaminergic compounds infused into the BLA had no effect on open-field or elevated plus-maze behaviour. The data show that histamine induces a dose-dependent mnemonic effect in rats and indicate that this reflects a role of endogenous histamine in the BLA mediated by H3 receptors.

Behavioral tagging of extinction learning.

Extinction of contextual fear in rats is enhanced by exposure to a novel environment at 1-2 h before or 1 h after extinction training. This effect is antagonized by administration of protein synthesis inhibitors anisomycin and rapamycin into the hippocampus, but not into the amygdala, immediately after either novelty or extinction training, as well as by the gene expression blocker 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole administered after novelty training, but not after extinction training. Thus, this effect can be attributed to a mechanism similar to synaptic tagging, through which long-term potentiation can be enhanced by other long-term potentiations or by exposure to a novel environment in a protein synthesis-dependent fashion. Extinction learning produces a tag at the appropriate synapses, whereas novelty learning causes the synthesis of plasticity-related proteins that are captured by the tag, strengthening the synapses that generated this tag.

Histaminergic ligands injected into the nucleus basalis magnocellularis differentially affect fear conditioning consolidation.

The role of the nucleus basalis magnocellularis (NBM) in fear conditioning encoding is well established. In the present report, we investigate the involvement of the NBM histaminergic system in consolidating fear memories. The NBM was injected bilaterally with ligands of histaminergic receptors immediately after contextual fear conditioning. Histaminergic compounds, either alone or in combination, were stereotaxically administered to different groups of adult male Wistar rats and memory was assessed as conditioned freezing duration 72 h after administration. This protocol prevents interference with NBM function during either acquisition or retrieval phases, hence restricting the effect of pharmacological manipulations to fear memory consolidation. The results presented here demonstrate that post-training H3 receptors (H3R) blockade with the antagonist/inverse agonist thioperamide or activation with immepip in the NBM potentiates or decreases, respectively, freezing response at retrieval. Thioperamide induced memory enhancement seems to depend on H2R, but not H1R activation, as the H2R antagonist zolantidine blocked the effect of thioperamide, whereas the H1R antagonist pyrilamine was ineffective. Furthermore, the H2R agonist ampthamine improved fear memory expression independently of the H3R agonist effect. Our results indicate that activation of post-synaptic H2R within the NBM by endogenous histamine is responsible for the potentiated expression of fear responses. The results are discussed in terms of activation of H3 auto- and heteroreceptors within the NBM and the differential effect of H3R ligands on fear memory consolidation in distinct brain regions.

Histamine reverses a memory deficit induced in rats by early postnatal maternal deprivation.

Early partial maternal deprivation causes long-lasting neurochemical, behavioral and brain structural effects. In rats, it causes a deficit in memory consolidation visible in adult life. Some of these deficits can be reversed by donepezil and galantamine, which suggests that they may result from an impairment of brain cholinergic transmission. One such deficit, representative of all others, is an impairment of memory consolidation, clearly observable in a one-trial inhibitory avoidance task. Recent data suggest a role of brain histaminergic systems in the regulation of behavior, particularly inhibitory avoidance learning. Here we investigate whether histamine itself, its analog SKF-91844, or various receptor-selective histamine agonists and antagonists given into the CA1 region of the hippocampus immediately post-training can affect retention of one-trial inhibitory avoidance in rats submitted to early postnatal maternal deprivation. We found that histamine, SKF-91844 and the H2 receptor agonist, dimaprit enhance consolidation on their own and reverse the consolidation deficit induced by maternal deprivation. The enhancing effect of histamine was blocked by the H2 receptor antagonist, ranitidine, but not by the H1 receptor antagonist pyrilamine or by the H3 antagonist thioperamide given into CA1 at doses known to have other behavioral actions, without altering locomotor and exploratory activity or the anxiety state of the animals. The present results suggest that the memory deficit induced by early postnatal maternal deprivation in rats may in part be due to an impairment of histamine mediated mechanisms in the CA1 region of the rat hippocampus.

Histaminergic mechanisms for modulation of memory systems.

Encoding for several memory types requires neural changes and the activity of distinct regions across the brain. These areas receive broad projections originating in nuclei located in the brainstem which are capable of modulating the activity of a particular area. The histaminergic system is one of the major modulatory systems, and it regulates basic homeostatic and higher functions including arousal, circadian, and feeding rhythms, and cognition. There is now evidence that histamine can modulate learning in different types of behavioral tasks, but the exact course of modulation and its mechanisms are controversial. In the present paper we review the involvement of the histaminergic system and the effects histaminergic receptor agonists/antagonists have on the performance of tasks associated with the main memory types as well as evidence provided by studies with knockout models. Thus, we aim to summarize the possible effects histamine has on modulation of circuits involved in memory formation.

Maternal dietary loads of α-tocopherol depress protein kinase C signaling and synaptic plasticity in rat postnatal developing hippocampus and promote permanent deficits in adult offspring.

Vitamin E (α-tocopherol) supplementation has been tested as prophylaxis against gestational disorders associated with oxidative damage. However, recent evidence showing that high maternal α-tocopherol intake can adversely affect offspring development raises concerns on the safety of vitamin E extradosages during pregnancy. Besides acting as an antioxidant, α-tocopherol depresses cell proliferation and modulates cell signaling through inhibiting protein kinase C (PKC), a kinase that is deeply involved in neural maturation and plasticity. Possible effects of α-tocopherol loads in the maturing brain, where PKC dysregulation is associated to developmental dysfunctions, are poorly known. Here, supranutritional doses of α-tocopherol were fed to pregnant and lactating dams to evaluate the effects on PKC signaling and morphofunctional maturation in offspring hippocampus. Results showed that maternal supplementation potentiates hippocampal α-tocopherol incorporation in offspring and leads to marked decrease of PKC phosphorylation throughout postnatal maturation, accompanied by reduced phosphorylation of growth-associated protein-43 and myristoylated alanine-rich C kinase substrate, two PKC substrates involved in neural development and plasticity. Although processes of neuronal maturation, synapse formation and targeting appeared unaffected, offspring of supplemented mothers displayed a marked reduction of long-term synaptic plasticity in juvenile hippocampus. Interestingly, this impairment persisted in adulthood, when a deficit in hippocampus-dependent, long-lasting spatial memory was also revealed. In conclusion, maternal supplementation with elevated doses of α-tocopherol can influence cell signaling and synaptic plasticity in developing hippocampus and promotes permanent adverse effects in adult offspring. The present results emphasize the need to evaluate the safety of supranutritional maternal intake of α-tocopherol in humans.