Modelos animales para el estudio de factores de vulnerabilidad en el contexto de desórdenes neuropsiquiátricos y de adicción a drogas

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Biológicas, leída el 11/12/2013Fac. de Ciencias BiológicasTRUEunpu

Maternal deprivation exacerbates the response to a high fat diet in a sexually dimorphic manner.

Maternal deprivation (MD) during neonatal life has diverse long-term effects, including affectation of metabolism. Indeed, MD for 24 hours during the neonatal period reduces body weight throughout life when the animals are maintained on a normal diet. However, little information is available regarding how this early stress affects the response to increased metabolic challenges during postnatal life. We hypothesized that MD modifies the response to a high fat diet (HFD) and that this response differs between males and females. To address this question, both male and female Wistar rats were maternally deprived for 24 hours starting on the morning of postnatal day (PND) 9. Upon weaning on PND22 half of each group received a control diet (CD) and the other half HFD. MD rats of both sexes had significantly reduced accumulated food intake and weight gain compared to controls when raised on the CD. In contrast, when maintained on a HFD energy intake and weight gain did not differ between control and MD rats of either sex. However, high fat intake induced hyperleptinemia in MD rats as early as PND35, but not until PND85 in control males and control females did not become hyperleptinemic on the HFD even at PND102. High fat intake stimulated hypothalamic inflammatory markers in both male and female rats that had been exposed to MD, but not in controls. Reduced insulin sensitivity was observed only in MD males on the HFD. These results indicate that MD modifies the metabolic response to HFD intake, with this response being different between males and females. Thus, the development of obesity and secondary complications in response to high fat intake depends on numerous factors

The maternal deprivation animal model revisited

Early life stress, in the form of MD (24 h at pnd 9), interferes with brain developmental trajectories modifying both behavioral and neurobiochemical parameters. MD has been reported to enhance neuroendocrine responses to stress, to affect emotional behavior and to impair cognitive function. More recently, changes in body weight gain, metabolic parameters and immunological responding have also been described. Present data give support to the fact that neuronal degeneration and/or astrocyte proliferation are present in specific brain regions, mainly hippocampus, prefrontal cortex and hypothalamus, which are particularly vulnerable to the effects of neonatal stress. The MD animal model arises as a valuable tool for the investigation of the brain processes occurring at the narrow time window comprised between pnd 9 and 10 that are critical for the establishment of brain circuitries critical for the regulation of behavior, metabolism and energy homeostasis. In the present review we will discuss three possible mechanisms that might be crucial for the effects of MD, namely, the rapid increase in glucocorticoids, the lack of the neonatal leptin surge, and the enhanced endocannabinoid signaling during the specific critical period of MD. A better understanding of the mechanisms underlying the detrimental consequences of MD is a concern for public health and may provide new insights into mental health prevention strategies and into novel therapeutic approaches in neuropsychiatry.Sin financiación8.580 JCR (2015) Q1, 3/51 Behavioral Sciences, 16/256 NeurosciencesUE

Sex-dependent effects of neonatal maternal deprivation on endocannabinoid levels in the adipose tissue: influence of diet

Maternal deprivation (MD) during neonatal life has diverse long-term effects, including modification of metabolism. We have previously reported that MD modifies the metabolic response to high-fat diet (HFD) intake, with this response being different between males and females, while previous studies indicate that in mice with HFD-induced obesity, endocannabinoid (EC) levels are markedly altered in various brown and white adipose tissue depots. Here, we analyzed the effects of MD (24 h at postnatal day 9), alone or in combination with a HFD from weaning until the end of the experiment in Wistar rats of both sexes. Brown and white perirenal and subcutaneous adipose tissues were collected and the levels of anandamide (AEA), 2-arachidonoylglycerol (2-AG), palmitoylethanolamide (PEA), and oleoylethanolamide (OEA) were determined. In males, MD increased the content of OEA in brown and 2-AG in subcutaneous adipose tissues, while in females the content of 2-AG was increased in perirenal fat. Moreover, in females, MD decreased AEA and OEA levels in perirenal and subcutaneous adipose tissues, respectively. HFD decreased the content of 2-AG in brown fat of both sexes and OEA in brown and subcutaneous adipose tissue of control females. In contrast, in subcutaneous fat, HFD increased AEA levels in MD males and OEA levels in control and MD males. The present results show for the first time that MD and HFD induce sex-dependent effects on the main ECs, AEA, and 2-AG, and of AEA-related mediators, OEA and PEA, in the rat brown and white (visceral and subcutaneous) adipose tissues

2-AG promotes the expression of conditioned fear via cannabinoid receptor type 1 on GABAergic neurons

Rationale The contribution of two major endocannabinoids, 2-arachidonoylglycerol (2-AG) and anandamide (AEA), in the regulation of fear expression is still unknown. Objectives We analyzed the role of different players of the endocannabinoid system on the expression of a strong auditory-cued fear memory in male mice by pharmacological means. Results The cannabinoid receptor type 1 (CB1) antagonist SR141716 (3 mg/kg) caused an increase in conditioned freezing upon repeated tone presentation on three consecutive days. The cannabinoid receptor type 2 (CB2) antagonist AM630 (3 mg/kg), in contrast, had opposite effects during the first tone presentation, with no effects of the transient receptor potential vanilloid receptor type 1 (TRPV1) antagonist SB366791 (1 and 3 mg/kg). Administration of the CB2 agonist JWH133 (3 mg/kg) failed to affect the acute freezing response, whereas the CB1 agonist CP55,940 (50 μg/kg) augmented it. The endocannabinoid uptake inhibitor AM404 (3 mg/kg), but not VDM11 (3 mg/kg), reduced the acute freezing response. Its co-administration with SR141716 or SB366791 confirmed an involvement of CB1 and TRPV1. AEA degradation inhibition by URB597 (1 mg/kg) decreased, while 2-AG degradation inhibition by JZL184 (4 and 8 mg/kg) increased freezing response. As revealed in conditional CB1- deficient mutants, CB1 on cortical glutamatergic neurons alleviates whereas CB1 on GABAergic neurons slightly enhances fear expression. Moreover, 2-AG fear-promoting effects depended on CB1 signaling in GABAergic neurons, while an involvement of glutamatergic neurons remained inconclusive due to the high freezing shown by vehicle-treated Glu-CB1-KO. Conclusions Our findings suggest that increased AEA levels mediate acute fear relief, whereas increased 2-AG levels promote the expression of conditioned fear primarily via CB1 on GABAergic neurons

Kilocalorie intake from the time of weaning (day 22 of age) until day 101 of life in males (A) and females (B).

<p>Total kilocalorie intake throughout the study (C). CtCD: controls on a control diet; CtHF: controls on a high fat diet from weaning onward; MDCD: maternally deprived rats on a control diet; MDHF: maternally deprived rats on a HFD from weaning onward. Significant differences: a: CtCD vs MDCD; b: CtCD vs CtHF; c: CtHF vs MDHF; d: MDCD vs MDHF. ***  =  ANOVA p<0.0001.</p

Serum levels of glucose (n = 10), insulin (n = 5), triglycerides (n = 11–12) and leptin (n = 12) at 35, 45, 65 and 85 days of age.

<p>CtCD: controls on a control diet; CtHF: controls on a high fat diet from weaning onward; MDCD: maternally deprived rats on a control diet; MDHF: maternally deprived rats on a HFD from weaning onward. a: different from CtCD of same sex; b: different from MDCD of same sex; c: different from CtHF of same sex; d: different from males of same treatment.</p

Hypothalamic mRNA levels of neuropeptide Y (NPY; A & B), Agouti related peptide (AgRP; C & D), proopiomelanocortin (POMC; E & F) and cocaine- and amphetamine regulated transcript (CART; G & H) in male (left column) and female (right column) rats.

<p>CtCD: controls on a control diet; CtHF: controls on a high fat diet from weaning onward; MDCD: maternally deprived rats on a control diet; MDHF: maternally deprived rats on a HFD from weaning onward. *  =  ANOVA p<0.05, NS  =  not significant.</p

Hypothalamic mRNA levels of interleukin (IL)-1β (A & B), IL-6 (C & D), tumor necrosis factor (TNF)-α (E & F), and silencer of cytokine signaling 3 (SOCS3; G & H) in male (left column) and female (right column) rats.

<p>CtCD: controls on a control diet; CtHF: controls on a high fat diet from weaning onward; MDCD: maternally deprived rats on a control diet; MDHF: maternally deprived rats on a HFD from weaning onward. *  =  ANOVA p<0.05, NS  =  not significant.</p