Impact of early high-fat diet consumption on different systems of memory

L‟obésité est principalement du à la surconsommation d‟aliments riches en énergie, en particulier les aliments hyperlipidiques (HL). En plus des comorbidités comme le diabète et les maladies cardiovasculaires, l‟obésité est associée à des troubles émotionnels et cognitifs. La prévalence de l‟obésité chez les enfants et les adolescents augmente sans cesse et ceci est inquiétant car ce sont des périodes cruciales pour la maturation de structures cérébrales comme l‟hippocampe et l‟amygdale, indispensables à la mise en place des processus cognitifs et émotionnels pour le restant de la vie. Il est donc déterminant d‟évaluer l‟impact de la consommation d‟un régime HL obésogène durant ces périodes développementales sur les processus cognitifs et émotionnels. Dans une première étude nous mettons en évidence chez le rat que l‟exposition à un régime HL durant la période périnatale (gestation et lactation) entraine l‟atrophie dendritique des neurones pyramidaux du CA1 de l‟hippocampe et de l‟amygdale basolatérale (BLA) des descendants adultes. Ces résultats sur l‟hippocampe enrichissent les données comportementales déjà existantes indiquant des altérations de la mémoire dépendante de l‟hippocampe suite au régime HL périnatal. Nous montrons également que les changements morphologiques du BLA s‟accompagnent d‟un déficit spécifique de la mémoire aversive olfactive, qui dépend fortement de l‟intégrité du BLA. Ceci démontre pour la première fois les effets délétères, cellulaires et comportementaux, d’un régime HL périnatal sur les fonctions amygdaliennes. La seconde étude se focalise sur les perturbations de la mémoire induites par la consommation d‟un régime HL pendant l‟adolescence et vise à approfondir la compréhension des mécanismes impliqués. Dans un premier temps, nous montrons que la consommation d‟un régime HL du sevrage à l‟âge adulte (couvrant l‟adolescence) chez la souris perturbe la consolidation de la mémoire de reconnaissance d‟objet (MRO) lorsque le contexte est nouveau lors de l‟apprentissage. Ceci s‟accompagne d‟une libération plus importante de glucocorticoïdes au niveau circulant et d‟endocannabinoides (eCB, anandamide en particulier) au niveau hippocampique chez les souris HL. Le blocage des récepteurs aux glucocorticoïdes (GR) ou des récepteurs aux cannabinoïdes de type 1 (CB1R) juste après l‟apprentissage améliore la MRO à long-terme des souris HL. Ces traitements normalisent également la sur-activation c-Fos de l‟hippocampe suite à l‟apprentissage chez les souris HL soulignant l‟importance de cette structure. En effet, la délétion spécifique des CB1R hippocampique améliore fortement la MRO à long-terme des souris HL et nous mettons en évidence que la plasticité synaptique in vivo de la voie CA3-CA1 hippocampique représente un mécanisme perturbé par l‟activation des CB1R suite à l‟apprentissage chez ces souris. Enfin l‟inactivation des neurones glutamatergique hippocampique par une approche pharmacogénétique (DREADD-Gi) améliore la MRO à long-terme chez les souris HL, de façon similaire au blocage ou à la délétion des CB1R suggérant une levée d‟inhibition de ces neurones par l‟activation des CB1R chez les souris HL qui conduirait à leur déficit de MRO à long-terme. Nos résultats indiquent que la consommation d’un régime HL pendant l’adolescence modifie le système eCB de l’hippocampe conduisant à des perturbations de la plasticité synaptique et de la consolidation de la mémoire. Dans leur ensemble ces données permettent d‟améliorer notre compréhension des effets délétères de l‟exposition précoces aux régimes HL obésogènes sur les fonctions mnésiques.Clinical and experimental studies have established that obesity, resulting mainly from consumption of energy-dense food such as high-fat diet (HFD), is associated with adverse cognitive and emotional outcomes. The prevalence of obesity during childhood and adolescence has reached epidemic levels. This is particularly worrisome since these periods are crucial for hippocampal and amygdala maturation, two brain structures necessary for shaping memory and emotional functions. It is thus critical to determine the impact of HFD exposure during these early developmental periods on memory and emotional processes. First, we show that perinatal HFD exposure (throughout gestation and lactation), leads to dendritic shrinkage of pyramidal neurons in the CA1 of the hippocampus but also in the basolateral amygdala (BLA) in adult rats. These results add to the growing literature indicating changes in hippocampal-dependent memory after perinatal HFD exposure. Regarding amygdala, perinatal HFD exposure specifically impairs odor aversion memory, a task highly dependent on BLA function, without affecting olfactory or malaise processing. These results are the first to show that perinatal HFD exposure impairs amygdala functions, at cellular and behavioral levels. Next, we investigated the cellular mechanisms underlying memory impairment induced by adolescent HFD consumption. We first show that HFD consumption from weaning to adulthood (covering adolescence) impairs long-term, but not short-term, object recognition memory (ORM) in novel context condition which was associated with higher circulating corticosterone and enhanced hippocampal endocannabinoid levels (anandamide in particular) in HFD-fed mice. Systemic post-training blockade of glucocorticoid receptors (GR) or cannabinoid receptors type 1 (CB1R) prevented HFD-induced memory deficits. These treatments also normalized training-induced c-Fos over-activation specifically in hippocampus in HFD group stressing the importance of this structure. Indeed, hippocampal CB1R deletion improved memory in HFD-fed mice. Moreover, we identified changes of in vivo hippocampal synaptic plasticity after training as a potential mechanism impaired by HFD in a CB1R-dependent manner. Finally, chemogenetic inhibition of hippocampal glutamatergic cells improved memory in HFD group similarly to CB1R deletion or blockade suggesting CB1R-dependent disinhibition of these neurons in HFD-fed mice. These results indicate that high-fat diet consumption during adolescence alters the hippocampal eCB system leading to impairment of hippocampal synaptic plasticity and deficit in recognition memory consolidation. Taken together, our results provide new evidences of how HFD consumption during early developmental periods exerts its deleterious effects on cognitive functions and identify the endocannabinoid system as a potential target for treating cognitive impairment associated with obesity

Impact de la consommation précoce d’un régime hyperlipidique obésogène sur différents systèmes de mémoire

Clinical and experimental studies have established that obesity, resulting mainly from consumption of energy-dense food such as high-fat diet (HFD), is associated with adverse cognitive and emotional outcomes. The prevalence of obesity during childhood and adolescence has reached epidemic levels. This is particularly worrisome since these periods are crucial for hippocampal and amygdala maturation, two brain structures necessary for shaping memory and emotional functions. It is thus critical to determine the impact of HFD exposure during these early developmental periods on memory and emotional processes. First, we show that perinatal HFD exposure (throughout gestation and lactation), leads to dendritic shrinkage of pyramidal neurons in the CA1 of the hippocampus but also in the basolateral amygdala (BLA) in adult rats. These results add to the growing literature indicating changes in hippocampal-dependent memory after perinatal HFD exposure. Regarding amygdala, perinatal HFD exposure specifically impairs odor aversion memory, a task highly dependent on BLA function, without affecting olfactory or malaise processing. These results are the first to show that perinatal HFD exposure impairs amygdala functions, at cellular and behavioral levels. Next, we investigated the cellular mechanisms underlying memory impairment induced by adolescent HFD consumption. We first show that HFD consumption from weaning to adulthood (covering adolescence) impairs long-term, but not short-term, object recognition memory (ORM) in novel context condition which was associated with higher circulating corticosterone and enhanced hippocampal endocannabinoid levels (anandamide in particular) in HFD-fed mice. Systemic post-training blockade of glucocorticoid receptors (GR) or cannabinoid receptors type 1 (CB1R) prevented HFD-induced memory deficits. These treatments also normalized training-induced c-Fos over-activation specifically in hippocampus in HFD group stressing the importance of this structure. Indeed, hippocampal CB1R deletion improved memory in HFD-fed mice. Moreover, we identified changes of in vivo hippocampal synaptic plasticity after training as a potential mechanism impaired by HFD in a CB1R-dependent manner. Finally, chemogenetic inhibition of hippocampal glutamatergic cells improved memory in HFD group similarly to CB1R deletion or blockade suggesting CB1R-dependent disinhibition of these neurons in HFD-fed mice. These results indicate that high-fat diet consumption during adolescence alters the hippocampal eCB system leading to impairment of hippocampal synaptic plasticity and deficit in recognition memory consolidation. Taken together, our results provide new evidences of how HFD consumption during early developmental periods exerts its deleterious effects on cognitive functions and identify the endocannabinoid system as a potential target for treating cognitive impairment associated with obesity.L‟obésité est principalement du à la surconsommation d‟aliments riches en énergie, en particulier les aliments hyperlipidiques (HL). En plus des comorbidités comme le diabète et les maladies cardiovasculaires, l‟obésité est associée à des troubles émotionnels et cognitifs. La prévalence de l‟obésité chez les enfants et les adolescents augmente sans cesse et ceci est inquiétant car ce sont des périodes cruciales pour la maturation de structures cérébrales comme l‟hippocampe et l‟amygdale, indispensables à la mise en place des processus cognitifs et émotionnels pour le restant de la vie. Il est donc déterminant d‟évaluer l‟impact de la consommation d‟un régime HL obésogène durant ces périodes développementales sur les processus cognitifs et émotionnels. Dans une première étude nous mettons en évidence chez le rat que l‟exposition à un régime HL durant la période périnatale (gestation et lactation) entraine l‟atrophie dendritique des neurones pyramidaux du CA1 de l‟hippocampe et de l‟amygdale basolatérale (BLA) des descendants adultes. Ces résultats sur l‟hippocampe enrichissent les données comportementales déjà existantes indiquant des altérations de la mémoire dépendante de l‟hippocampe suite au régime HL périnatal. Nous montrons également que les changements morphologiques du BLA s‟accompagnent d‟un déficit spécifique de la mémoire aversive olfactive, qui dépend fortement de l‟intégrité du BLA. Ceci démontre pour la première fois les effets délétères, cellulaires et comportementaux, d’un régime HL périnatal sur les fonctions amygdaliennes. La seconde étude se focalise sur les perturbations de la mémoire induites par la consommation d‟un régime HL pendant l‟adolescence et vise à approfondir la compréhension des mécanismes impliqués. Dans un premier temps, nous montrons que la consommation d‟un régime HL du sevrage à l‟âge adulte (couvrant l‟adolescence) chez la souris perturbe la consolidation de la mémoire de reconnaissance d‟objet (MRO) lorsque le contexte est nouveau lors de l‟apprentissage. Ceci s‟accompagne d‟une libération plus importante de glucocorticoïdes au niveau circulant et d‟endocannabinoides (eCB, anandamide en particulier) au niveau hippocampique chez les souris HL. Le blocage des récepteurs aux glucocorticoïdes (GR) ou des récepteurs aux cannabinoïdes de type 1 (CB1R) juste après l‟apprentissage améliore la MRO à long-terme des souris HL. Ces traitements normalisent également la sur-activation c-Fos de l‟hippocampe suite à l‟apprentissage chez les souris HL soulignant l‟importance de cette structure. En effet, la délétion spécifique des CB1R hippocampique améliore fortement la MRO à long-terme des souris HL et nous mettons en évidence que la plasticité synaptique in vivo de la voie CA3-CA1 hippocampique représente un mécanisme perturbé par l‟activation des CB1R suite à l‟apprentissage chez ces souris. Enfin l‟inactivation des neurones glutamatergique hippocampique par une approche pharmacogénétique (DREADD-Gi) améliore la MRO à long-terme chez les souris HL, de façon similaire au blocage ou à la délétion des CB1R suggérant une levée d‟inhibition de ces neurones par l‟activation des CB1R chez les souris HL qui conduirait à leur déficit de MRO à long-terme. Nos résultats indiquent que la consommation d’un régime HL pendant l’adolescence modifie le système eCB de l’hippocampe conduisant à des perturbations de la plasticité synaptique et de la consolidation de la mémoire. Dans leur ensemble ces données permettent d‟améliorer notre compréhension des effets délétères de l‟exposition précoces aux régimes HL obésogènes sur les fonctions mnésiques

Maternal high-fat diet leads to hippocampal and amygdala dendritic remodeling in adult male offspring

Early-life exposure to calorie-dense food, rich in fat and sugar, contributes to the increasing prevalence of obesity and its associated adverse cognitive and emotional outcomes at adulthood. It is thus critical to determine the impact of such nutritional environment on neurobehavioral development. In animals, maternal high-fat diet (HFD) consumption impairs hippocampal function in adult offspring, but its impact on hippocampal neuronal morphology is unknown. Moreover, the consequences of perinatal HFD exposure on the amygdala, another important structure for emotional and cognitive processes, remain to be established. In rats, we show that adult offspring from dams fed with HFD (45% from fat, throughout gestation and lactation) exhibit atrophy of pyramidal neuron dendrites in both the CA1 of the hippocampus and the basolateral amygdala (BLA). Perinatal HFD exposure also impairs conditioned odor aversion, a task highly dependent on BLA function, without affecting olfactory or malaise processing. Neuronal morphology and behavioral alterations elicited by perinatal HFD are not associated with body weight changes but with higher plasma leptin levels at postnatal day 15 and at adulthood. Taken together, our results suggest that perinatal HFD exposure alters hippocampal and amygdala neuronal morphology which could participate to memory alterations at adulthood

Maternal high-fat diet and early life stress differentially modulate spine density and dendritic morphology in the medial prefrontal cortex of juvenile and adult rats

The medial prefrontal cortex (mPFC) is a key area for the regulation of numerous brain functions including stress response and cognitive processes. This brain area is also particularly affected by adversity during early life. Using an animal model in rats, we recently demonstrated that maternal exposure to a high-fat diet (HFD) prevents maternal separation (MS)-induced gene expression alterations in the developing PFC and attenuates several long-term deleterious behavioral effects of MS. In the present study, we ask whether maternal HFD could protect mPFC neurons of pups exposed to early life stress by examining dendritic morphology and spine density in juvenile [postnatal day (PND) 21] and adult rats submitted to MS. Dams were fed either a control or an HFD throughout gestation and lactation, and pups were submitted to MS from PND2 to PND14. We report that maternal HFD prevents MS-induced spine loss at PND21 and dendritic atrophy at adulthood. Furthermore, we show in adult MS rats that PFC-dependent memory extinction deficits are prevented by maternal HFD. Finally, perinatal HFD exposure reverses gut leakiness following stress in pups and seems to exert an anti-stress effect in dams. Overall, our work demonstrates that maternal HFD affects the developing brain and suggests that nutrition, possibly through gut-brain interactions, could modulate mPFC sensitivity to early stress.Environnement psychosocial précoce, empreintes biologiques et épigénétiques et état de santé à l'âge adult

Corticosteroid-binding globulin deficiency specifically impairs contextual and recognition memory consolidation in male mice

Background/Aims: Glucocorticoids are essential in modulating memory processes of emotionally arousing experiences and we have shown that corticosteroid-binding globulin (CBG) influences glucocorticoid delivery to the brain. Here, we investigated the role of CBG in contextual and recognition long-term memory according to stress intensity. Method: We used adult male mice totally deficient in CBG (Cbg KO) or brain-specific Cbg KO (Cbg(Camk) KO) to examine their performance in contextual fear conditioning (CFC) and au-ditory fear conditioning, both at short (1 h) and long-term (24 h). Long-term memory in Cbg KO was further analyzed in conditioned odor aversion and in novel object recognition task (NORT) with different paradigms, that is, with and without prior habituation to the context, with a mild or strong stressor applied during consolidation. In the NORT experiments, total and free glucocorticoid levels were measured during consolidation. Results: Impaired memory was observed in the Cbg KO but not in the Cbg(Camk) KO in the CFC and the NORT without habituation when tested 24 h later. However, Cbg KO displayed normal behavior in the NORT with previous habituation and in the NORT with a mild stressor. In condition of the NORT with a strong stressor, Cbg KO retained good 24 h memory performance while controls were impaired. Total and free glucocorticoids levels were always higher in controls than in Cbg KO except in NORT with mild stressor where free glucocorticoids were equivalent to controls. Conclusions: These data indicate that circulating but not brain CBG influences contextual and recognition long-term memory in relation with glucocorticoid levels

Effect of juvenile high-fat diet consumption on mesolimbic dopaminergic system

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