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

Gut microbiota and brain function: an evolving field in neuroscience

There is a growing appreciation of the importance of gut microbiota to health and disease. This has been driven by advances in sequencing technology and recent findings demonstrating the important role of microbiota in common health disorders such as obesity. Moreover, the potential role of gut microbiota in influencing brain function, behavior, and mental health has attracted the attention of neuroscientists and psychiatrists. At the 29th International College of Neuropsychopharmacology (CINP) World Congress held in Vancouver, Canada, in June 2014, a group of experts presented the symposium, “Gut microbiota and brain function: Relevance to psychiatric disorders” to review the latest findings in how gut microbiota may play a role in brain function, behavior, and disease. The symposium covered a broad range of topics, including gut microbiota and neuroendocrine function, the influence of gut microbiota on behavior, probiotics as regulators of brain and behavior, and imaging the gut-brain axis in humans. This report provides an overview of these presentations

Gut Microbes and the Brain: Paradigm Shift in Neuroscience

The discovery of the size and complexity of the human microbiome has resulted in an ongoing reevaluation of many concepts of health and disease, including diseases affecting the CNS. A growing body of preclinical literature has demonstrated bidirectional signaling between the brain and the gut microbiome, involving multiple neurocrine and endocrine signaling mechanisms. While psychological and physical stressors can affect the composition and metabolic activity of the gut microbiota, experimental changes to the gut microbiome can affect emotional behavior and related brain systems. These findings have resulted in speculation that alterations in the gut microbiome may play a pathophysiological role in human brain diseases, including autism spectrum disorder, anxiety, depression, and chronic pain. Ongoing large-scale population-based studies of the gut microbiome and brain imaging studies looking at the effect of gut microbiome modulation on brain responses to emotion-related stimuli are seeking to validate these speculations. This article is a summary of emerging topics covered in a symposium and is not meant to be a comprehensive review of the subject

cAMP Response Element-Binding Protein Is Essential for the Upregulation of Brain-Derived Neurotrophic Factor Transcription, But Not the Behavioral or Endocrine Responses to Antidepressant Drugs

Antidepressant drugs activate the cAMP signal transduction pathway through a variety of monoamine neurotransmitter receptors. Recently, molecular studies have identified a role for cAMP response element-binding protein (CREB) in the mechanism of action of chronically administered antidepressant drugs. However, the function of CREB in the behavioral and endocrine responses to these drugs has not been thoroughly investigated. We have used CREB-deficient mice to study the effects of two antidepressants, desipramine (DMI) and fluoxetine (FLX), in behavioral, endocrine, and molecular analyses. Behaviorally, CREB-deficient mice and wild-type mice respond similarly to DMI and FLX administration in the forced swim test and tail suspension test. Furthermore, the ability of DMI to suppress an acute corticosterone response after swim stress is maintained in CREB-deficient mice. However, upregulation of a molecular target of CREB, BDNF, is abolished in the CREBdeficient mice after chronic administration of DMI. These data are the first to demonstrate that CREB activation is upstream of BDNF mechanistically in response to antidepressant drug treatment. Therefore, although behavioral and endocrine responses to antidepressants may occur by CREB-independent mechanisms, CREB is critical to target gene regulation after chronic drug administration, which may contribute to long-term adaptations of the system to antidepressant drug treatment

Therapeutic targeting in the silent era: advances in non-viral siRNA delivery

Gene silencing using RNA-interference, first described in mammalian systems almost a decade ago, is revolutionizing therapeutic target validation efforts both in vitro and in vivo. Moreover, the potential for using short interfering RNA (siRNA) as a therapy in its own right is also progressing at a significant pace. However, the widespread use of such approaches is contingent on having appropriate systems to achieve clinically appropriate, safe, and efficient delivery of siRNA. There are many physicochemical and biological barriers to such delivery, and a growing emphasis on the design and characterisation of non-viral technologies that will overcome these barriers and expedite targeted delivery. This review discusses the considerations and challenges associated with use of siRNA-based therapeutics, including stability and off-target effects. Speculation is made on the properties of an ideal delivery system and the non-viral delivery approaches used to date, both in vitro and in vivo, are classified and discussed. Moreover, the ability of cyclodextrin-based delivery vectors to fulfil many of the criteria of an ideal delivery construct is also elaborated

Streaking single-electron ionization in open-shell molecules driven by X-ray pulses

We obtain continuum molecular wavefunctions for open-shell molecules in the Hartree-Fock framework. We do so while accounting for the singlet or triplet total spin symmetry of the molecular ion, that is, of the open-shell orbital and the initial orbital where the electron ionizes from. Using these continuum wavefunctions, we obtain the dipole matrix elements for a core electron that ionizes due to single-photon absorption by a linearly polarized X-ray pulse. After ionization from the X-ray pulse, we control or streak the electron dynamics using a circularly polarized infrared (IR) pulse. For a high intensity IR pulse and photon energies of the X-ray pulse close to the ionization threshold of the $1{\sigma}$ or $2{\sigma}$ orbitals, we achieve control of the angle of escape of the ionizing electron by varying the phase delay between the X-ray and IR pulses. For a low intensity IR pulse, we obtain final electron momenta distributions on the plane of the IR pulse and we find that many features of these distributions correspond to the angular patterns of electron escape solely due to the X-ray pulse.Comment: 13 pages, 7 figure

Born this way: Hippocampal neurogenesis across the lifespan

The capability of the mammalian brain to generate new neurons through the lifespan has gained much attention for the promise of new therapeutic possibilities especially for the aging brain. One of the brain regions that maintains a neurogenesis-permissive environment is the dentate gyrus of the hippocampus. Here, new neurons are generated from a pool of multipotent neural progenitor cells to become fully functional neurons that are integrated into the brain circuitry. A growing body of evidence points to the fact that neurogenesis in the adult hippocampus is necessary for certain memory processes, and in mood regulation, while alterations in hippocampal neurogenesis have been associated with a myriad of neurological and psychiatric disorders. More recently, evidence has come to light that new neurons may differ in their vulnerability to environmental and disease-related influences depending on the time during the life course at which they are exposed. Thus, it has been the topic of intense research in recent years. In this review, we will discuss the complex process and associated functional relevance of hippocampal neurogenesis during the embryonic/postnatal period and in adulthood. We consider the implications of hippocampal neurogenesis during the developmentally critical periods of adolescence and older age. We will further consider the literature surrounding hippocampal neurogenesis and its functional role during these critical periods with a view to providing insight into the potential of harnessing neurogenesis for health and therapeutic benefit

Transient inactivation of the infralimbic cortex induces antidepressant-like effects in the rat

Affective disorders are among the main causes of disability worldwide, yet the underlying pathophysiology remains poorly understood. Recently, landmark neuroimaging studies have shown increased metabolic activity in Brodmann Area 25 (BA25) in depressed patients. Moreover, functional inactivation of this region using deep brain stimulation alleviated depressive symptoms in severely depressed patients. Thus, we examined the effect of a similar manipulation, pharmacological inactivation of the infralimbic cortex, the rodent correlate of BA25, in an animal model of antidepressant activity: the modified rat forced swim test. Transient inactivation of the infralimbic cortex using muscimol reduced immobility, an antidepressant-like effect in the test. Importantly, this activity was not the result of a general increase in locomotor activity. Activation of the infralimbic cortex using bicuculline did not alter behaviour. Finally, we examined the effect of muscimol in animals bred for high anxiety-related behaviour, which also display elevated depression-related behaviour. Transient inactivation of the infralimbic cortex decreased the high inborn depression-like behaviour of these rats. These results show that it is possible to replicate findings from a clinical trial in a rodent model. Further, they support the use of the forced swim test to gain greater understanding of the neurocircuitry involved in depression and antidepressant-action

11-β hydroxysteroid type 1 knockout mice display an antidepressant-like phenotype in the forced swim test

Objective 11-dehydroxysteroid dehydrogenase (HSD) types 1 and 2, enzymes are involved in the activation and inactivation of glucocorticoids in vivo, respectively. Indirect evidence implicates two enzymes in the aetiology of depression but no study has directly assessed the potential role of 11 -HSD1 in animal tests. Methods We assessed 11 -HSD1 knockout mice in the forced swim test (FST), tail suspension test (TST) and for locomotor activity. Results Genetic ablation of the 11-HSD1 gene results in an antidepressant-like phenotype in the FST; the most widely utilised animal test of antidepressant activity, but not in the related TST. This may be related to the different biological substrates underlying these tests. The decreased FST immobility was not due to alterations in general activity. Conclusions Taken together these results suggest that 11-HSD1 may play an important role in depression-related behaviours and further studies are necessary to fully characterise its role in such behaviour

Deletion of TLX and social isolation impairs exercise-induced neurogenesis in the adolescent hippocampus

Adolescence is a sensitive period of neurodevelopment during which life experiences and the surrounding environment can have profound effects on the brain. Neurogenesis is a neurodevelopmental process of generating functional neurons from neural stem cells. Hippocampal neurogenesis occurs throughout the lifespan and has been shown to play a role in learning, memory and in mood regulation. In adulthood it is influenced by extrinsic environmental factors such as exercise and stress. Intrinsic factors that regulate hippocampal neurogenesis include the orphan nuclear receptor TLX (Nr2e1) which is primarily expressed in the neurogenic niches of the brain. While mechanisms regulating adult hippocampal neurogenesis have been widely studied, less is known on how hippocampal neurogenesis is affected during adolescence. Thus, the aim of this study was to investigate the influence of both TLX and isolation stress on exercise-induced increases in neurogenesis in running and sedentary conditions during adolescence. Single- (i.e. isolation stress) wild type and Nr2e1-/- or pair-housed wild type mice were housed in sedentary conditions or allowed free access to running wheels for 3 weeks during the adolescent period. A reduction of neuronal survival was evident in mice lacking TLX, and exercise did not increase hippocampal neurogenesis in these Nr2e1-/- mice. This suggests that TLX is necessary for the pro-neurogenic effects of exercise during adolescence. Interestingly, although social isolation during adolescence did not affect hippocampal neurogenesis, it prevented an exercise-induced increase in neurogenesis in the ventral hippocampus. Together these data demonstrate the importance of intrinsic and extrinsic factors in promoting an exercise-induced increase in neurogenesis at this key point in life. This article is protected by copyright. All rights reserved