Interactions between genes and environment are recognized to play a critical role in modulating the development of the organism. More in details early maternal environment seems to be a key factor in shaping neuro-behavioral development; the mother-infant bond is the strongest and more common social relationship in mammal species and phylogenetically highly conserved. Experimental evidence demonstrated that maternal behavior may act on the regulation of genetic expression; in adult life, the offspring that had received high levels of maternal cares showed lower anxiety, less ACTH and Corticosterone production, less aging effect on hyppocampus and more immune activity in response to stress. In the present experiments we investigated the interaction between early maternal environment and specific genetic background, in relation to sex on metabolism and behaviour. We examined two different genetically modified mice models; the first one is a mouse model characterized by a conditional knock-out of the Y1 receptor in the excitatory neurons of the forebrain; the second one is a knockin mouse model of selective loss of the VGF peptide TLQP-21. To test the hypothesis that the effects of gene deletion may vary in relation to early maternal environment, in the first experiment male and female, Npy Ko and control mice were fostered at birth to dams that displayed high or low levels of maternal care (CD1 swiss, FVB – C57/Bl6, Balb/c respectively). As adults mice were tested for emotional, aggressive and social behavior and metabolic changes in response to standard or high fat diets. In the second experiment we performed a detailed analysis of the effect of early maternal environment on control animals of the Npy Y1r KO model. In the third experiment we observed maternal behavior and reproductive success in ΔTLQP-21 heterozygotes or homozygotes breeders and characterized their offspring by an analysis of emotional and depression-like behaviors in adult males and females. Overall the results of the first study showed that males, but not females, had an increase in axiety-like behavior and weighted less than their controls, but only when reared by foster mothers displaying high levels of maternal care. In the second experiment, we demonstrated that early maternal environment affected offspring development but its impact can not be ascribed entirely to the variation in maternal cares; in fact also maternal milk quality/quantity and nutritional factors could be important variables influencing behavior and metabolism in adult’s life. Lastly, results in the third study indicated that the mutation in TLQP21 gene influence maternal behavior, with mutant or heterozygotes breeders displaying lower amount of maternal care (defined by the time spent in the arched back position) when compared with wild type mice. Such a difference affected the offspring subsequent behavioral phenotype as adults, particularly emotional behaviour and sex related differences . Further study will be necessary to investigate the role of nutrition and maternal milk in metabolic and behavioural development of offspring in both NPY KO and WT animals, and to better understand the role of early maternal environment in ΔTLQP-21 mouse. The present findings, however, highlight the importance to take into consideration and control for the complex interaction between genes, early maternal environment and sex-related effects when working with GM mouse models to uncover specific gene functions.

Le interazioni gene-ambiente svolgono un ruolo critico nella modulazione dello sviluppo dell’organismo: in particolare l’ambiente materno precoce sembra essere un fattore chiave dello sviluppo neuro-comportamentale. Il legame tra la madre e il figlio infatti è considerato la relazione sociale più comune e duratura nei mammiferi, filogeneticamente conservato tra le diverse specie. Evidenze sperimentali indicano che l’ambiente materno precoce può modulare la regolazione dell’espressione genica; diversi studi hanno dimostrato che animali che avevano ricevuto maggiori cure materne durante il primo periodo post nascita, presentavano minori livelli di ansia, minore produzione di ACTH e corticosterone, minore invecchiamento nell’ippocampo e maggiore attività immunitaria in risposta allo stress. Negli esprimenti condotti abbiamo approfondito come l’interazione tra ambiente materno precoce e lo specifico background genetico, in relazione al sesso, agisca sul metabolismo e il comportamento. Abbiamo esaminato quindi due diversi modelli murini con modificazioni geniche: il primo è un modello caratterizzato da un knockout condizionale per il recettore Y1r nei neuroni eccitatori del proencefalo; il secondo è un knockout selettivo per TLQP21 (ΔTLQP-21), peptide derivato di VGF. Per testare l’ipotesi che gli effetti della delezione genica possono variare in relazione all’ambiente materno precoce, nel primo esperimento Npy KO e controlli di entrambi i sessi sono stati dati in adozione alla nascita a madri ad alto o basso grado di cure materne (rispettivamente CD1 swiss, FVB – C57/Bl6, Balb/c). In età adulta i topi sono stati sottoposti a test comportamentali per valutare l’aspetto emozionale, sociale ed aggressivo, e a test metabolici in risposta a dieta standard o ad alto contenuto di grassi. Nel secondo esperimento abbiamo eseguito un’analisi dettagliata dell’effetto dell’ambiente materno precoce sugli animali controllo del modello Npy Y1r KO. Nel terzo esperimento infine abbiamo osservato il comportamento materno e il successo riproduttivo in topi ΔTLQP-21 eterozigoti o omozigoti, ed eseguito una caratterizzazione della prole analizzando comportamento emozionale e simil-depressivo negli individui adulti di entrambi i sessi. In generale i risultati del primo studio hanno mostrato che i maschi, ma non le femmine, avevano un aumento dei comportamenti simil-ansiosi e pesavano meno dei loro rispettivi controlli solo quando allevati da madri adottive ad alto grado di cure materne. Nel secondo esperimento abbiamo dimostrato che l’ambiente materno agisce sullo sviluppo della prole ma l’impatto non è ascrivibile soltanto alle variazioni delle cure materne; infatti anche la quantità e la qualità del latte materno e fattori nutrizionali potrebbero essere variabili importanti che influenzano il comportamento e il metabolismo in età adulta. Infine, i risultati del terzo studio hanno indicato che la mutazione nel gene TLQP21 influenza il comportamento materno: genitori che avevano fenotipo mutante ed eterozigote mostravano un livello minore di cure materne (definito dal tempo trascorso nella posizione di arched back) se confrontati con topi wild-type. Tale differenza ha effetto anche sul fenotipo comportamentale degli animali adulti, in particolare riguardo al comportamento emozionale e alle relative differenze sessuali. Saranno dunque necessari ulteriori studi per comprendere il ruolo della nutrizione e del latte materno nello sviluppo comportamentale della prole negli animali Ko e Wt del modello Npy, e per capire in maniera dettagliata quale sia il ruolo dell’ambiente materno nei topi ΔTLQP-21.I risultati ottenuti sottolineano quanto sia importante prendere in considerazione la complessa interazione tra gene, ambiente materno precoce ed effetti legati al sesso quando si lavora con modelli murini geneticamente modificati per identificare funzioni specifiche dei geni.

Impatto dell’ambiente materno precoce e del sesso sul comportamento e metabolismo in due modelli murini KO / Giada Caviola , 2020 Mar 19. 32. ciclo, Anno Accademico 2018/2019.

Impatto dell’ambiente materno precoce e del sesso sul comportamento e metabolismo in due modelli murini KO

CAVIOLA, GIADA
2020

Abstract

Interactions between genes and environment are recognized to play a critical role in modulating the development of the organism. More in details early maternal environment seems to be a key factor in shaping neuro-behavioral development; the mother-infant bond is the strongest and more common social relationship in mammal species and phylogenetically highly conserved. Experimental evidence demonstrated that maternal behavior may act on the regulation of genetic expression; in adult life, the offspring that had received high levels of maternal cares showed lower anxiety, less ACTH and Corticosterone production, less aging effect on hyppocampus and more immune activity in response to stress. In the present experiments we investigated the interaction between early maternal environment and specific genetic background, in relation to sex on metabolism and behaviour. We examined two different genetically modified mice models; the first one is a mouse model characterized by a conditional knock-out of the Y1 receptor in the excitatory neurons of the forebrain; the second one is a knockin mouse model of selective loss of the VGF peptide TLQP-21. To test the hypothesis that the effects of gene deletion may vary in relation to early maternal environment, in the first experiment male and female, Npy Ko and control mice were fostered at birth to dams that displayed high or low levels of maternal care (CD1 swiss, FVB – C57/Bl6, Balb/c respectively). As adults mice were tested for emotional, aggressive and social behavior and metabolic changes in response to standard or high fat diets. In the second experiment we performed a detailed analysis of the effect of early maternal environment on control animals of the Npy Y1r KO model. In the third experiment we observed maternal behavior and reproductive success in ΔTLQP-21 heterozygotes or homozygotes breeders and characterized their offspring by an analysis of emotional and depression-like behaviors in adult males and females. Overall the results of the first study showed that males, but not females, had an increase in axiety-like behavior and weighted less than their controls, but only when reared by foster mothers displaying high levels of maternal care. In the second experiment, we demonstrated that early maternal environment affected offspring development but its impact can not be ascribed entirely to the variation in maternal cares; in fact also maternal milk quality/quantity and nutritional factors could be important variables influencing behavior and metabolism in adult’s life. Lastly, results in the third study indicated that the mutation in TLQP21 gene influence maternal behavior, with mutant or heterozygotes breeders displaying lower amount of maternal care (defined by the time spent in the arched back position) when compared with wild type mice. Such a difference affected the offspring subsequent behavioral phenotype as adults, particularly emotional behaviour and sex related differences . Further study will be necessary to investigate the role of nutrition and maternal milk in metabolic and behavioural development of offspring in both NPY KO and WT animals, and to better understand the role of early maternal environment in ΔTLQP-21 mouse. The present findings, however, highlight the importance to take into consideration and control for the complex interaction between genes, early maternal environment and sex-related effects when working with GM mouse models to uncover specific gene functions.
Impact of early maternal environment and sex on behaviour and metabolism in two KO mouse models
19-mar-2020
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1200998
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