MiRNA-34 and stress response

Psychiatric disorders are known to result from a strong interaction between genetic predisposition and environmental factors, mainly exposure to stressful events. Environmental events can modulate genes expression, possibly via epigenetic mechanisms, and affect onset/expression of a disease [1]. Epigenetic mechanisms include, among others, post-transcriptional regulation by non-coding RNAs such as microRNAs (miRNAs). MiRNAs are small non-coding RNAs predicted to regulate hundreds of targets and to be engaged in every biological process [2]. Thanks to their ability to fine-tune gene expression, miRNAs can control gene expression patterns favoring organism’s adaptation to internal and environmental (external) factors [3], such as stressful events

Animal models of compulsive eating behavior

In industrialized nations, overeating is a significant problem leading to overweight, obesity, and a host of related disorders; the increase in these disorders has prompted a significant amount of research aimed at understanding their etiology. Eating disorders are multifactorial conditions involving genetic, metabolic, environmental, and behavioral factors. Considering that compulsive eating in the face of adverse consequences characterizes some eating disorders, similar to the way in which compulsive drug intake characterizes drug-addiction, it might be considered an addiction in its own right. Moreover, numerous review articles have recently drawn a connection between the neural circuits activated in the seeking/intake of palatable food and drugs of abuse. Based on this observation, “food addiction” has emerged as an area of intense scientific research and accumulating evidence suggests it is possible to model some aspects of food addiction in animals. The development of well-characterized animal models would advance our understanding of the etiologic neural factors involved in eating disorders, such as compulsive overeating, and it would permit to propose targeted pharmacological therapies. However, to date, little evidence has been reported of continued food seeking and intake despite its harmful consequences in rats and mice

Effects of lack of microRNA-34 on the neural circuitry underlying the stress response and anxiety

Stress-related psychiatric disorders, including anxiety, are complex diseases that have genetic, and environmental causes. Stressful experiences increase the release of prefrontal amygdala neurotransmitters, a response that is relevant to cognitive, emotional, and behavioral coping. Moreover, exposure to stress elicits anxiety-like behavior and dendritic remodeling in the amygdala. Members of the miR-34 family have been suggested to regulate synaptic plasticity and neurotransmission processes, which mediate stress-related disorders. Using mice that harbored targeted deletions of all 3 members of the miR-34-family (miR-34-TKO), we evaluated acute stress-induced basolateral amygdala (BLA)-GABAergic and medial prefrontal cortex (mpFC) aminergic outflow by intracerebral in vivo microdialysis. Moreover, we also examined fear conditioning/extinction, stress-induced anxiety, and dendritic remodeling in the BLA of stress-exposed TKO mice. We found that TKO mice showed resilience to stress-induced anxiety and facilitation in fear extinction. Accordingly, no significant increase was evident in aminergic prefrontal or amygdala GABA release, and no significant acute stress-induced amygdalar dendritic remodeling was observed in TKO mice. Differential GRM7, 5-HT2C, and CRFR1 mRNA expressionwas noted in the mpFC and BLA between TKO andWT mice. Our data demonstrate that the miR-34 has a critical function in regulating the behavioral and neurochemical response to acute stress and in inducing stress-related amygdala neuroplasticity

Mouse model of panic disorder: Vulnerability to early environmental instability is strain-dependent.

AbstractEarly life experiences and genetic background shape phenotypic variation. Several mouse models based on early treatments have evaluated short‐ and long‐term phenotypic alterations and explored their molecular mechanisms. The instability of maternal cues was used to model human separation anxiety in outbred mice, one of the etiopathogenetic factors that predict panic disorder (PD). Application of the repeated cross‐fostering (RCF) protocol to inbred strains (C57 and DBA) allowed us to measure differential responses to the same experimental manipulation. Ultrasounds emitted during isolation indicated that after RCF, pups from both strains lose their ability to be comforted by nest cues, but the frequency modulation of separation calls increased in RCF‐C57 and decreased in RCF‐DBA mice. No strain‐specific difference in olfactory ability explained these responses in RCF‐exposed mice. Rather, disruption of the infant‐mother bond may differentially affect separation calls in the two strains. Moreover, the RCF‐associated increased respiratory response to hypercapnia–an endophenotype of human PD documented among mice outbred strains–was replicated in the C57 strain only. We suggest that RCF‐induced instability of the early environment affects emotionality and respiratory physiology differentially, depending on pups' genetic background. These strain‐specific responses provide a lead to understand differential vulnerability to emotional disorders

Early life adversity affecting the attachment bond alters ventral tegmental area transcriptomic patterning and behavior almost exclusively in female mice

Early life experiences that affect the attachment bond formation can alter developmental trajectories and result in pathological outcomes in a sex-related manner. However, the molecular basis of sex differences is quite unknown. The dopaminergic system originating from the ventral tegmental area has been proposed to be a key mediator of this process.Here we exploited a murine model of early adversity (Repeated Cross Fostering, RCF) to test how interfering with the attachment bond formation affects the VTA-related functions in a sex-specific manner.Through a comprehensive behavioral screening, within the NiH RDoC framework, and by next-generation RNA-Seq experiments, we analyzed the long-lasting effect of RCF on behavioral and transcriptional profiles related to the VTA, across two different inbred strains of mouse in both sexes.We found that RCF impacted to an extremely greater extent VTA-related behaviors in females than in males and this result mirrored the transcriptional alterations in the VTA that were almost exclusively observed in females. The sexual dimorphism was conserved across two different inbred strains in spite of their divergent long lasting consequences of RCF exposure.Our data suggest that to be female primes a sub-set of genes to respond to early environmental perturbations.This is, to the best of our knowledge, the first evidence of an almost exclusive effect of early life experiences on females, thus mirroring the extremely stronger impact of precocious aversive events reported in clinical studies in women

Long-term effects of early environment on the brain: Lesson from rodent models

The postnatal period is characterized by extensive neuronal plasticity, synaptic organization, and remod-eling. High neuroplasticity renders the brain sensitive to the remodeling effects induced by environmentalfactors, such as exposure to adversity, which can imprint neurochemical, neuroendocrine, morphological,and behavioral changes.Early experiences that influence developmental trajectories during maturation of the brain can have awide range of long-lasting effects, modulating stress-coping strategies in adult life and inducing vulner-ability or resilience to psychopathologies, depending on the gene × later experience interplay.Future studies will clarify how manipulation of the early environment induces these effects acting ongenetic and epigenetic factors

Linking drug and food addiction: an overview of the shared neural circuits and behavioral phenotype

Despite a lack of agreement on its definition and inclusion as a specific diagnosable disturbance, the food addiction construct is supported by several neurobiological and behavioral clinical and preclinical findings. Recognizing food addiction is critical to understanding how and why it manifests. In this overview, we focused on those as follows: 1. the hyperpalatable food effects in food addiction development; 2. specific brain regions involved in both food and drug addiction; and 3. animal models highlighting commonalities between substance use disorders and food addiction. Although results collected through animal studies emerged from protocols differing in several ways, they clearly highlight commonalities in behavioral manifestations and neurobiological alterations between substance use disorders and food addiction characteristics. To develop improved food addiction models, this heterogeneity should be acknowledged and embraced so that research can systematically investigate the role of specific variables in the development of the different behavioral features of addiction-like behavior in preclinical models

Food seeking in spite of harmful consequences

In industrialized nations, overeating is a significant problem leading to overweight, obesity, and a host of related disorders; the increase in these disorders has prompted a significant amount of research aimed at understanding their etiology. Eating disorders are multifactorial conditions involving genetic, metabolic, environmental, and behavioral factors. Considering that compulsive eating in the face of adverse consequences characterizes some eating disorders, similar to the way in which compulsive drug intake characterizes drug addiction, it might be considered an addiction in its own right. Moreover, numerous review articles have recently drawn a connection between the neural circuits activated in the seeking/intake of palatable food and drugs of abuse. Based on this observation, food addiction has emerged as an area of intense scientific research, and accumulating evidence suggests that it is possible to model some aspects of food addiction in animals. The development of well-characterized animal models would advance our understanding of the etiologic neural factors involved in eating disorders, such as compulsive overeating, and it would permit to propose targeted pharmacological therapies. However, to date, little evidence has been reported of continued food seeking and intake despite its harmful consequences in rats and mice. © 2013 Springer Science+Business Media, LLC

Interactions between experience, genotype and sex in the development of individual coping strategies

Coping strategies, the first line of defense against adversities, develop through experience. There is consistent evidence that both genotype and sex contribute to the development of dysfunctional coping, leading to maladaptive outcomes of adverse experiences or to adaptive coping that fosters rapid recovery even from severe stress. However, how these factors interact to influence the development of individual coping strategies is just starting to be investigated. In the following review, we will consider evidence that experience, sex, and genotype influence the brain circuits and neurobiological processes involved in coping with adversities and discuss recent results pointing to the specific effects of the interaction between early experiences, genotype, and stress in the development of functional and dysfunctional coping styles

Interaction Between Genetic And Environmental Factors Promotes Eating Disorders Altering Expression And Function Of Dopamine, Serotonin And Norepinephrine Receptors

Eating disorders are multifactorial conditions involving genetic, metabolic, environmental, and behavioral factors. Although animal studies cannot reproduce the complex psychosomatic features of human eating disorders, can be useful to separately examine the elements of the homeostatic and motivational impairments associated with compulsive eating behaviors. Drugs of abuse and palatable food intake show behavioral similarities and common neurobiological adaptations have been proposed to be involved in both drug and food related-disorders (Volkow and Wise, 2005). Compulsive drug intake in the face of adverse consequences is a hallmark feature of addiction and compulsive drug seeking has been shown to emerge only following an extended history of drug-taking (Vanderschuren and Everitt, 2004). Similarly, compulsive eating emerges following extended access to a palatable diet (Johnson and Kenny, 2010). Finally, stress exposure influences both the propensity to take drugs and food intake. Dopamine is a neurotransmitter critically involved in the reward and motivational aspects of feeding and D2 receptors have received particular attention (Wang et al., 2001; Davis et al 2009). However, recent reviews have focused on central monoamine systems in eating disorders, such serotonin and norepinephrine (Hainer et al , 2006; Kaye, 2008). Here we show that interaction between extended access to chocolate and chronic stress is able to transform adaptive food seeking/intake behavior into compulsive eating in DBA/2J mice (previously shown by Patel and coworkers, 2006, to be characterized by high impulsivity), but not in C57BL/6J mice. Moreover, we find strong alterations of dopamine, serotonin and norepinephrine receptors expression in three brain areas (medial prefrontal cortex, nucleus accumbens, dorsal striatum) critically involved in food-related motivated behavior. The animal model proposed here could be a good tool for understanding how environmental factors interact with genetic vulnerability to promote the development of eating disorders altering expression and function of dopamine, serotonin and norepinephrine receptors