Reduced expression of the serotonin transporter impacts mitochondria in a sexually dimorphic manner.

Neuropsychiatric and neurodevelopmental disorders are complex conditions that arise from a variety of interacting genetic and environmental factors. Among these factors, altered serotonergic signalling and mitochondrial dysfunction are strongly implicated, with a growing body of evidence to suggesting that serotonergic signalling is an important regulator of mitochondrial biogenesis. The serotonin transporter (SERT) functions to regulate synaptic 5-HT, and human allelic variants of the serotonin reuptake transporter-linked polymorphic region (5-HTTLPR) are associated with reduced SERT expression and increased susceptibility for developing neuropsychiatric disorders.

The role of the dopamine D1 receptor in anticipatory pleasure and social play.

Social play is a highly rewarding activity seen across mammalian species that is vital for neurobehavioural development. Dysfunctions in social play are seen across psychiatric and neurodevelopmental disorders positing the importance of understanding the neurobiological mechanisms underlying social play. A multitude of neurotransmitter systems have been implicated in social play, with the present study focused on the role of dopamine, specifically the dopamine D1 receptor.

The effect of mixed tobacco monoamine oxidase inhibitors in animal models relevant to tobacco dependence.

Rationale: Tobacco monoamine oxidase (MAO) inhibitors have long been suspected of influencing tobacco dependence, but direct evidence of their effects has been difficult to obtain. Recently we have identified two new groups of monoamine oxidase inhibitors, hydroquinones and polyunsaturated fatty acids (linoleic and linolenic acid), abundant in tobacco smoke.

Objectives: To test, in relevant animal models, whether the combined effect of these inhibitors is sufficient to affect addictive responses to nicotine.

Development of DuoMYC: a synthetic cell penetrant miniprotein that efficiently inhibits the oncogenic transcription factor MYC.

The master regulator transcription factor MYC is implicated in numerous human cancers, and its targeting is a long-standing challenge in drug development. MYC is a typical 'undruggable' target, with no binding pockets on its DNA binding domain and extensive intrinsically disordered regions. Rather than trying to target MYC directly with classical modalities, here we engineer synthetic miniproteins that can bind to MYC's target DNA, the enhancer box (E-Box), and potently inhibit MYC-driven transcription.

Synthetic Peptides: Promising Modalities for the Targeting of Disease-Related Nucleic Acids.

DNA and RNA play pivotal roles in life processes by storing and transferring genetic information, modulating gene expression, and contributing to essential cellular machinery such as ribosomes. Dysregulation and mutations in nucleic acid-related processes are implicated in numerous diseases. Despite the critical impact on health of nucleic acid mutations or dysregulation, therapeutic compounds addressing these biomolecules remain limited.

The Changes of Histone Methylation Induced by Adolescent Social Stress Regulate the Resting-State Activity in mPFC.

Early-life stress can lead to sustained alterations in regional resting-state brain functions, but the underlying molecular mechanism remains unclear. Stress can also induce sustained changes in epigenetic modifications across brain regions, which are not limited to a few genes; rather, they often tend to produce global levels of change. The functional implication of these changes also remains to be elucidated.

Dopamine D1 receptor and effort-based decision making in rats: The moderating effect of sex.

Dopamine is a modulating factor in effort-based decision-making, and emerging evidence from pharmacological research suggests that the dopamine D1 receptor is the primary regulator. Given the limited selectivity of pharmacological tools, we further explored this hypothesis using dopamine D1 mutant (DAD1) rats which have a specific genetic reduction in functional D1 receptors. Moreover, given the strong focus on males in neuroscience research in general and in the role of D1 receptors in effort-based learning, we compared both sexes in the present study.

Preweaning environmental enrichment alters neonatal ultrasonic vocalisations in a rat model for prenatal infections.

Objective: Maternal infections are a well-known risk factor for neurodevelopmental defects. Such defects are associated with a range of symptoms, and environmental enrichment (EE) could be a promising approach to rehabilitate these. We used the well-established prenatal poly I:C (polyinosinic-polycytidylic acid) model in rats to examine the effects of preweaning EE on rat pups' ultrasonic vocalisations (USVs) when separated from their mothers.

Genetics and epigenetics: paternal adolescent ethanol consumption in serotonin transporter knock-out rats and offspring sensitivity to ethanol.

Rationale: Alcohol use disorder (AUD) is shown to have an overall heritability of around 50%. One of the genes associated with AUD is SLC6A4 (solute carrier family 6 member A4) which codes for the serotonin transporter (SERT). The study looked at serotonin dysfunction on ethanol consumption in adolescents and the subsequent intergenerational effects of drinking by using a rat model: SERT (regular functioning), SERT (50% transporter reduction) and SERT (complete reduction).

Biologically Active Compounds Present in Tobacco Smoke: Potential Interactions Between Smoking and Mental Health.

Tobacco dependence remains one of the major preventable causes of premature morbidity and mortality worldwide. There are well over 8,000 compounds present in tobacco and tobacco smoke, but we do not know what effect, if any, many of them have on smokers. Major interest has been on nicotine, as well as on toxic and carcinogenic effects and several major and minor components of tobacco smoke responsible for the negative health effects of smoking have been elucidated.

Sex bias in the serotonin transporter knockout model: Implications for neuropsychiatric disorder research.

Serotonergic signalling is implicated in the aetiology of many neuropsychiatric disorders. The serotonin reuptake transporter (SERT) is an important regulator of synaptic serotonin, being an important pharmacological target with genetic variants implicated with risk of developing neuropsychiatric disorders. Animal models have played an important role in understanding the genetic risk and role of SERT function in brain development having highlighted sex differences in incidence, presentation, and treatment efficacy, however, sex bias due to unequal representation of sexes in research remains a significant issue.

The serotonin reuptake transporter modulates mitochondrial copy number and mitochondrial respiratory complex gene expression in the frontal cortex and cerebellum in a sexually dimorphic manner.

Neuropsychiatric and neurodevelopmental disorders such as major depressive disorder (MDD) and autism spectrum disorder (ASD) are complex conditions attributed to both genetic and environmental factors. There is a growing body of evidence showing that serotonergic signaling and mitochondrial dysfunction contribute to the pathophysiology of these disorders and are linked as signaling through specific serotonin (5-HT) receptors drives mitochondrial biogenesis. The serotonin transporter (SERT) is important in these disorders as it regulates synaptic serotonin and therapeutically is the target of selective serotonin reuptake inhibitors which are a major class of anti-depressant drug.

Genetic Knockout of the Serotonin Reuptake Transporter Results in the Reduction of Dendritic Spines in In vitro Rat Cortical Neuronal Culture.

Dysregulation of the serotonergic system has been reported to have a significant role in several neurological disorders including depression, autism and substance abuse disorders. Changes in the expression of the serotonin transporter (SERT) through polymorphisms in the regulatory regions of the SERT gene have been associated, but not yet been conclusively linked to, neuropsychiatric disorders. In turn, dendritic spine structure and function are critical for neuronal function and the disruption of dendritic spine formation at glutamatergic synapses is a hallmark of several neuropsychiatric disorders.

mPFC GABAergic transmission mediated the role of BDNF signaling in cognitive impairment but not anxiety induced by adolescent social stress.

Depression with comorbid anxiety or cognitive symptoms can vary in terms of symptoms, pathophysiology and antidepressant efficacy, but the underlying neurobiological mechanisms remain to be elucidated. Previous studies from our group and others have shown that as a classic animal model of depression, adolescent social stress (ASS) could stably induce a variety of emotional and cognitive alterations in adult animals, and accompanied by transcriptional decrease in brain-derived neurotrophic factor (BDNF) total and promoter IV levels in the medial prefrontal cortex (mPFC). The present study further identified the GABAergic synaptic and molecular changes downstream of BDNF signaling impairment in the mPFC and roles in various behavioral phenotypes induced by ASS.

The role of dopamine D1 receptors in MDMA-induced memory impairments.

(±) 3,4-Methylenedioxymethamphetamine (MDMA) is a recreationally abused psychostimulant that impairs memory performance. This effect is often attributed to a working memory impairment resulting from compromised serotonin systems. However, recent evidence from non-human animal experimental studies suggests that acute MDMA may indirectly impair memory performance through overstimulation of dopamine (DA) D1 receptors, which increases perseverative responding during memory tasks.

Evaluation of i-Motif Formation in the Serotonin Transporter-Linked Polymorphic Region.

Neuropsychiatric disorders such as major depressive disorder (MDD) arise from a complex set of genetic and environmental factors. The serotonin transporter (SERT) is a key regulator of synaptic serotonin (5-HT), and its inhibition is an important pharmacological target for treating MDD. The SERT-linked polymorphic region (5-HTTLPR) contains two major variants (short and long) that have been implicated in modulating susceptibility to MDD by altering the level of expression of SERT.

Transient upregulation of immune activity induced by adolescent social stress is involved in cognitive deficit in adult male mice and early intervention with minocycline.

Increasing evidence shows that the developmental perturbation of immune activity can lead to long-lasting neurodevelopmental and behavioral abnormalities. In our previous study, we found that deficiencies of microglia and TNFα in the medial prefrontal cortex (mPFC) were involved in the impairment of cognitive flexibility induced by adolescent social stress in adult mice. It remains unclear how and when immune changes occur following adolescent stress exposure and whether it is possible to prevent the delayed occurrence of cognitive impairment through early immune intervention.

Deficiencies of microglia and TNFα in the mPFC-mediated cognitive inflexibility induced by social stress during adolescence.

The crucial roles played by microglia and their release of cytokines in the regulation of brain maturation are increasingly being recognized. Adolescence is a unique period characterized by continued brain maturation, especially in the area of the prefrontal cortex. Our previous studies showed that adolescent social stress induced impairment in extradimensional set-shifting (EDS), a core component of cognitive flexibility mediated by the medial prefrontal cortex (mPFC) in adult mice.

Characteristics of pro- and anti-inflammatory cytokines alteration in PTSD patients exposed to a deadly earthquake.

Background: Many studies have shown that the disturbance of pro-inflammatory and/or anti-inflammatory cytokines is involved in the modulation of traumatic stress and related psychiatric disorders, typically posttraumatic stress disorder (PTSD). However, the specific immune alterations associated with PTSD symptoms are still unclear. The present study compared levels of pro- and anti-inflammatory cytokines between PTSD and non-PTSD controls, and investigated the relationships of immune changes with PTSD symptomatology.

A genetic deletion of the serotonin transporter differentially influences the behavioural effects of MDMA.

Background: While (±)-3,4-methylenedioxymethamphetamine (MDMA) primarily induces serotonin release, it also affects dopamine and noradrenaline transmission. It is, however, unclear what role each of these neurotransmitters play in the behavioural profile of MDMA.

Methods: In this study we used the drug discrimination (DD) and the acoustic startle (ASR) paradigms to examine the behaviour of rats with and without a genetic deletion of the serotonin transporter SERT (SERT and SERT rats).