Resistance to Early-Life Stress in Mice: Effects of Genetic Background and Stress Duration

Early-life stress can induce marked behavioral and physiological impairments in adulthood including cognitive deficits, depression, anxiety, and gastrointestinal dysfunction. Although robust rat models of early-life stress exist there are few established effective paradigms in the mouse. Genetic background and protocol parameters used are two critical variables in such model development. Thus we investigated the impact of two different early-life stress protocols in two commonly used inbred mouse strains. C57BL/6 and innately anxious BALB/c male mice were maternally deprived 3 h daily, either from postnatal day 1 to 14 (protocol 1) or 6 to 10 (protocol 2). Animals were assessed in adulthood for cognitive performance (spontaneous alternation behavior test), anxiety [open-field, light/dark box (L/DB), and elevated plus maze (EPM) tests], and depression-related behaviors (forced swim test) in addition to stress-sensitive physiological changes. Overall, the results showed that early-life stressed mice from both strains displayed good cognitive ability and no elevations in anxiety. However, paradoxical changes occurred in C57BL/6 mice as the longer protocol (protocol 1) decreased anxiety in the L/DB and increased exploration in the EPM. In BALB/c mice there were also limited effects of maternal separation with both separation protocols inducing reductions in stress-induced defecation and protocol 1 reducing the colon length. These data suggest that, independent of stress duration, mice from both strains were on the whole resilient to the maladaptive effects of early-life stress. Thus maternal separation models of brain–gut axis dysfunction should rely on either different stressor protocols or other strains of mice

Evaluation of reward processes in an animal model of depression

Rationale: Anhedonia is a core symptom of major depression. Deficits in reward function, which underlie anhedonia, can be readily assessed in animals. Therefore, anhedonia may serve as an endophenotype for understanding the neural circuitry and molecular pathways underlying depression. Objective: Surprisingly, there is scant knowledge regarding alterations in brain reward function after olfactory bulbectomy (OB), an animal model which results in a behavioural syndrome responsive to chronic antidepressant treatment. Therefore, the present studies aimed to assess reward function after bulbectomy. Materials and methods: The present study utilized sucrose preference, cocaine-induced hyperlocomotion and intra-cranial self-stimulation (ICSS) responding to examine reward processes in the OB model. Results: Bulbectomized animals showed a marked preference (>90%) for 0.8% sucrose solution compared with water; similar to the preference exhibited by sham controls. Importantly, there were pronounced deficits in brain reward function, as assessed using ICSS, which lasted 8days before returning to baseline levels. Furthermore, bulbectomized animals were hyper-responsive to the locomotor stimulating properties of an acute and a repeated cocaine regimen. However, no difference in ICSS facilitation was observed in response to an acute cocaine injection. Conclusions: Taken together, these results suggest that bulbectomized rats display alterations in brain reward function, but these changes are not long-lasting and thus, not amenable to investigating the effects of pharmacological interventions. However, given that OB animals are hypersensitive to drugs of abuse, bulbectomy may be an appropriate inducing factor for the development of animal models of co-morbid depression and drug dependenc

The microbiome-gut-brain axis in health and disease

Gut microbes are capable of producing most neurotransmitters found in the human brain. While these neurotransmitters primarily act locally in the gut, modulating the enteric nervous system, evidence is now accumulating to support the view that gut microbes through multiple mechanisms can influence central neurochemistry and behavior. This has been described as a fundamental paradigm shift in neuroscience. Bifidobacteria for example can produce and increase plasma levels of the serotonin precursor tryptophan, which is fundamental in regulating mood, appetite and gastrointestinal function. Certain Lactobacilli have been shown to produce gamma-aminobutyric acid (GABA) and to alter brain GABA receptor expression and behavior. IBS is regarded as the prototypic disorder of the brain-gut-microbiota axis which can be responsive to probiotic therapy. Recently, the concept of a psychobiotic has been introduced in the literature. A psychobiotic is a bacteria which when ingested in adequate amounts can have a positive mental health benefit. Translational studies indicate that certain bacteria may impact upon stress responses and cognitive functioning. Manipulating the gut microbiota with psychobiotics, prebiotics or even antibiotics offers a novel approach to altering brain function and treating gut-brain axis disorders such as depression and autism

A Gut Feeling about GABA: Focus on GABAB Receptors

γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the body and hence GABA-mediated neurotransmission regulates many physiological functions, including those in the gastrointestinal (GI) tract. GABA is located throughout the GI tract and is found in enteric nerves as well as in endocrine-like cells, implicating GABA as both a neurotransmitter and an endocrine mediator influencing GI function. GABA mediates its effects via GABA receptors which are either ionotropic GABAA or metabotropic GABAB. The latter which respond to the agonist baclofen have been least characterized, however accumulating data suggest that they play a key role in GI function in health and disease. Like GABA, GABAB receptors have been detected throughout the gut of several species in the enteric nervous system, muscle, epithelial layers as well as on endocrine-like cells. Such widespread distribution of this metabotropic GABA receptor is consistent with its significant modulatory role over intestinal motility, gastric emptying, gastric acid secretion, transient lower esophageal sphincter relaxation and visceral sensation of painful colonic stimuli. More intriguing findings, the mechanisms underlying which have yet to be determined, suggest GABAB receptors inhibit GI carcinogenesis and tumor growth. Therefore, the diversity of GI functions regulated by GABAB receptors makes it a potentially useful target in the treatment of several GI disorders. In light of the development of novel compounds such as peripherally acting GABAB receptor agonists, positive allosteric modulators of the GABAB receptor and GABA producing enteric bacteria, we review and summarize current knowledge on the function of GABAB receptors within the GI tract

Bovine serum albumin as the dominant form of dietary protein reduces subcutaneous fat mass, plasma leptin and plasma corticosterone in high fat-fed C57/BL6J mice

Acknowledgements The authors thank Harriett Schellekens from the University College Cork and Paula O’Connor from Teagasc Moorepark Food Research Centre for their assistance in procuring laboratory space and equipment. The present study was funded by Teagasc. B. L. M. was funded by the Walsh Fellowship Program. J. R. S. was supported by a 1000-talents professorship from the Chinese government. The funding bodies had no input on the design of the study or in the interpretation of the data.Peer reviewedPublisher PD

A Survey of LIDAR Technology and Its Use in Spacecraft Relative Navigation

This paper provides a survey of modern LIght Detection And Ranging (LIDAR) sensors from a perspective of how they can be used for spacecraft relative navigation. In addition to LIDAR technology commonly used in space applications today (e.g. scanning, flash), this paper reviews emerging LIDAR technologies gaining traction in other non-aerospace fields. The discussion will include an overview of sensor operating principles and specific pros/cons for each type of LIDAR. This paper provides a comprehensive review of LIDAR technology as applied specifically to spacecraft relative navigation. HE problem of orbital rendezvous and docking has been a consistent challenge for complex space missions since before the Gemini 8 spacecraft performed the first successful on-orbit docking of two spacecraft in 1966. Over the years, a great deal of effort has been devoted to advancing technology associated with all aspects of the rendezvous, proximity operations, and docking (RPOD) flight phase. After years of perfecting the art of crewed rendezvous with the Gemini, Apollo, and Space Shuttle programs, NASA began investigating the problem of autonomous rendezvous and docking (AR&D) to support a host of different mission applications. Some of these applications include autonomous resupply of the International Space Station (ISS), robotic servicing/refueling of existing orbital assets, and on-orbit assembly.1 The push towards a robust AR&D capability has led to an intensified interest in a number of different sensors capable of providing insight into the relative state of two spacecraft. The present work focuses on exploring the state-of-the-art in one of these sensors - LIght Detection And Ranging (LIDAR) sensors. It should be noted that the military community frequently uses the acronym LADAR (LAser Detection And Ranging) to refer to what this paper calls LIDARs. A LIDAR is an active remote sensing device that is typically used in space applications to obtain the range to one or more points on a target spacecraft. As the name suggests, LIDAR sensors use light (typically a laser) to illuminate the target and measure the time it takes for the emitted signal to return to the sensor. Because the light must travel from the source, t

Resilience priming: translational models for understanding resiliency and adaptation to early life adversity

Despite the increasing attention to early life adversity and its long-term consequences on health, behavior, and the etiology of neurodevelopmental disorders, our understanding of the adaptations and interventions that promote resiliency and rescue against such insults are underexplored. Specifically, investigations of the perinatal period often focus on negative events/outcomes. In contrast, positive experiences (i.e. enrichment/parental care//healthy nutrition) favorably influence development of the nervous and endocrine systems. Moreover, some stressors result in adaptations and demonstrations of later-life resiliency. This review explores the underlying mechanisms of neuroplasticity that follow some of these early life experiences and translates them into ideas for interventions in pediatric settings. The emerging role of the gut microbiome in mediating stress susceptibility is also discussed. Since many negative outcomes of early experiences are known, it is time to identify mechanisms and mediators that promote resiliency against them. These range from enrichment, quality parental care, dietary interventions and those that target the gut microbiota

Interleukin-6 Modulates Colonic Transepithelial Ion Transport in the Stress-Sensitive Wistar Kyoto Rat

Immunological challenge stimulates secretion of the pro-inflammatory cytokine interleukin (IL)-6, resulting in variety of biological responses. In the gastrointestinal tract, IL-6 modulates the excitability of submucosal neurons and stimulates secretion into the colonic lumen. When considered in the context of the functional bowel disorder, irritable bowel syndrome (IBS), where plasma levels of IL-6 are elevated, this may reflect an important molecular mechanism contributing to symptom flares, particularly in the diarrhea-predominant phenotype. In these studies, colonic ion transport, an indicator of absorption and secretion, was assessed in the stress-sensitive Wistar Kyoto (WKY) rat model of IBS. Mucosa-submucosal colonic preparations from WKY and control Sprague Dawley (SD) rats were mounted in Ussing chambers and the basal short circuit current (I(SC)) was electrophysiologically recorded and compared between the strains. Exposure to IL-6 (1 nM) stimulated a secretory current of greater amplitude in WKY as compared to SD samples. Furthermore, the observed IL-6-mediated potentiation of secretory currents evoked by veratridine and capsaicin in SD rats was blunted in WKY rats. Exposure to IL-6 also stimulated an increase in transepithelial resistance in both SD and WKY colonic tissue. These studies demonstrate that the neuroexcitatory effects of IL-6 on submucosal plexi have functional consequences with alterations in both colonic secretory activity and permeability. The IL-6-induced increase in colonic secretory activity appears to neurally mediated. Thus, local increases in IL-6 levels and subsequent activation of enteric neurons may underlie alterations in absorpto-secretory function in the WKY model of IBS

Whey protein isolate decreases murine stomach weight and intestinal length and alters the expression of Wnt signalling-associated genes

Acknowledgements K. N. N. was supported by the Teagasc Vision Programme on Obesity (RMIS5974). L. M. was supported by the Teagasc Walsh Fellowship. J. R. S. was supported by a 1000-talents professorship from the Chinese government. The funding bodies had no input on the design of the study or in the interpretation of the data. The authors’ contributions are as follows: L. M., J. R. S., J. F. C. and K. N. N. designed the study; K. N. N. and J. F. C. obtained ethical approval for the study; L. M. performed the experiments; L. M. and J. R. S. analysed the data; L. M. generated the figures. All authors contributed to the drafting of the manuscript. All authors approved the final version for submission. The authors declare that there is no competing interest.Peer reviewedPublisher PD

Early-life stress induces persistent alterations in 5-HT1A receptor and serotonin transporter mRNA expression in the adult rat brain

Early-life experience plays a major role in the stress response throughout life. Neonatal maternal separation (MS) is an animal model of depression with an altered serotonergic response. We hypothesize that this alteration may be caused by differences in 5-HT(1A) receptor and serotonin transporter (SERT) mRNA expression in brain areas involved in the control of emotions, memory, and fear as well as in regions controlling the central serotonergic tone. To test this, Sprague–Dawley rats were subjected to MS for 3 h daily during postnatal days 2–12. As control, age matched rats were non-separated (NS) from their dams. When animals reached adulthood (11–13 weeks) brain was extracted and mRNA expression of 5-HT(1A) receptor in amygdala, hippocampus and dorsal raphé nucleus (DRN) and SERT in the DRN was analyzed through in situ hybridisation. Densitometric analysis revealed that MS increased 5-HT(1A) receptor mRNA expression in the amygdala, and reduced its expression in the DRN, but no changes were observed in the hippocampus in comparison to NS controls. Also, MS reduced SERT mRNA expression in the DRN when compared to NS rats. These results suggest that early-life stress induces persistent changes in 5-HT(1A) receptor and SERT mRNA expression in key brain regions involved in the development of stress-related psychiatric disorders. The reduction in SERT mRNA indicates an alteration that is in line with clinical findings such as polymorphic variants in individuals with higher risk of depression. These data may help to understand how early-life stress contributes to the development of mood disorders in adulthood