The effects of brain serotonin deficiency on the behavioral and neurogenesis-promoting effects of voluntary exercise in tryptophan hydroxylase 2 (R439H) knock-in mice.

Exercise is known to reduce depression and anxiety symptoms. Although the cellular and molecular mechanisms underlying this effect remain unknown, exercise-induced increases in neurotransmitter release and hippocampal neurogenesis have been hypothesized to play key roles. One neurotransmitter that has been implicated in both antidepressant-like effects and the regulation of hippocampal neurogenesis is serotonin (5-HT).

Genetic loss of the dopamine transporter significantly impacts behavioral and molecular responses to sub-chronic stress in mice.

Dopaminergic neurotransmission has emerged as a critical determinant of stress susceptibility and resilience. Although the dopamine transporter (DAT) is known to play a key role in maintaining dopamine (DA) homeostasis, its importance for the regulation of stress susceptibility remains largely unknown. Indeed, while numerous studies have examined the neurochemical and behavioral consequences of genetic loss of DAT, very few have compared responses to stress in wild-type and DAT-knockout (KO) animals.

Estrogen administration and withdrawal in a model of hormone-simulated pregnancy lead to alterations in behavior and gene expression but do not induce depression-like phenotypes in mice.

Pregnancy and the post-partum period are associated with substantial fluctuations in hormone levels and are frequently associated with significant stress. Many individuals also experience affective disturbances during the peri‑partum period, including anxiety, the 'baby blues,' and post-partum depression. However, the extent to which these affective changes result from rapidly altering hormone levels, increased stress, or the combination of both remains largely unknown.

Chronic, but not sub-chronic, stress increases binge-like alcohol consumption in male and female c57BL6 mice.

Stress is known to contribute to mental illness and alcohol use disorders, which are highly prevalent and lead to considerable disability. These stress-related disorders are characterized by significant sex differences, which remain poorly understood. Preclinical research comparing the effects of stress in males and females has the potential to provide new insights into the neurobiology of these conditions.

Early life maternal separation induces sex-specific antidepressant-like responses but has minimal effects on adult stress susceptibility in mice.

Early life stress is known to increase the risk of depression and anxiety disorders, which are highly prevalent conditions that disproportionately affect women. However, the results of preclinical studies have been mixed, with some work suggesting that early life stress promotes anxiety-like behavior and/or increases susceptibility to subsequent stressors, and other research suggesting that early life stress reduces anxiety-like behavior and/or confers resilience to subsequent stress exposure. It is likely that factors such as sex and the timing and severity of early life and adult stress exposure dictate whether a particular early life experience promotes adaptive vs.

Brain serotonin deficiency and fluoxetine lead to sex-specific effects on binge-like food consumption in mice.

Rationale: Although pharmacotherapies are often effective in reducing binge eating in conditions such as bulimia nervosa and binge eating disorder, subsets of patients do not benefit sufficiently from existing treatments, and the reasons for treatment failure remain unclear.

Objectives: This study aimed to evaluate whether genetic reductions in brain serotonin influence binge eating and/or the ability of fluoxetine, a selective serotonin reuptake inhibitor, to reduce binge eating in mice.

Methods: This study used a validated model of binge-like consumption of high-fat diet to compare binge-like food intake in control and fluoxetine-treated wild-type and serotonin-deficient mice from the tryptophan hydroxylase 2 (R439H) knock-in line.

Sub-chronic stress induces similar behavioral effects in male and female mice despite sex-specific molecular adaptations in the nucleus accumbens.

Women are more likely than men to suffer from major depression and anxiety disorders, a fact that is thought to depend in part on sex differences in stress susceptibility. Consistent with this, several preclinical stress paradigms have been reported to exert differential effects in males vs. females.

The Effects of Brain Serotonin Deficiency on Responses to High Fat Diet in Female Mice.

Clinical studies have reported an increased risk of depression and anxiety disorders among individuals who are obese, and women are more likely than men to suffer from depression, anxiety, and obesity. However, the effects of obesity-promoting diets on depression- and anxiety-like behavior remain controversial. A recent study from our group used the tryptophan hydroxylase 2 (R439H) knock-in mouse line to evaluate the impact of genetic brain serotonin (5-HT) deficiency on behavioral responses to high fat diet (HFD) in male mice.

Brain 5-HT Deficiency Prevents Antidepressant-Like Effects of High-Fat-Diet and Blocks High-Fat-Diet-Induced GSK3β Phosphorylation in the Hippocampus.

Obesity is associated with an increased risk of depression and anxiety disorders, but the nature of the relationship(s) between obesity and mental illness remains highly controversial. Some argue that depression and anxiety lead to increased consumption of "comfort foods," the intake of which reduces negative affect and promotes obesity. In contrast, others have theorized that negative affect results from chronic excessive consumption of highly palatable foods.

Slow-release delivery enhances the pharmacological properties of oral 5-hydroxytryptophan: mouse proof-of-concept.

5-hydroxytryptophan (5-HTP) has shown therapeutic promise in a range of human CNS disorders. But native 5-HTP immediate release (IR) is poorly druggable, as rapid absorption causes rapid onset of adverse events, and rapid elimination causes fluctuating exposure. Recently, we reported that 5-HTP delivered as slow-release (SR) in mice augmented the brain pro-serotonergic effect of selective serotonin reuptake inhibitors (SSRIs), without the usual adverse events associated with 5-HTP IR.

Brain-wide Electrical Spatiotemporal Dynamics Encode Depression Vulnerability.

Brain-wide fluctuations in local field potential oscillations reflect emergent network-level signals that mediate behavior. Cracking the code whereby these oscillations coordinate in time and space (spatiotemporal dynamics) to represent complex behaviors would provide fundamental insights into how the brain signals emotional pathology. Using machine learning, we discover a spatiotemporal dynamic network that predicts the emergence of major depressive disorder (MDD)-related behavioral dysfunction in mice subjected to chronic social defeat stress.

Brain-region-specific Molecular Responses to Maternal Separation and Social Defeat Stress in Mice.

The association between stress and mental illness has been well documented, but the molecular consequences of repeated exposure to stress have not been completely identified. The present study sought to elucidate the combinatorial effects of early-life maternal separation stress and adult social defeat stress on alterations in signal transduction and gene expression that have been previously implicated in susceptibility to psychosocial stress. Molecular analyses were performed in the prelimbic/infralimbic cortex, amygdala, and nucleus accumbens, three brain regions that have been suggested to play critical roles in determining stress responses.

SSRI Augmentation by 5-Hydroxytryptophan Slow Release: Mouse Pharmacodynamic Proof of Concept.

Drugs, notably SSRIs, that elevate brain extracellular 5-HT (5-HTExt) are antidepressants. Unfortunately, most patients fail to remit. Multipronged clinical evidence suggests that elevating 5-HTExt beyond the SSRI effect enhances antidepressant efficacy, but previous such drug strategies had prohibitive limitations.

p75 Neurotrophin Receptor Regulates Energy Balance in Obesity.

Obesity and metabolic syndrome reflect the dysregulation of molecular pathways that control energy homeostasis. Here, we show that the p75 neurotrophin receptor (p75(NTR)) controls energy expenditure in obese mice on a high-fat diet (HFD). Despite no changes in food intake, p75(NTR)-null mice were protected from HFD-induced obesity and remained lean as a result of increased energy expenditure without developing insulin resistance or liver steatosis.

Brain 5-HT deficiency increases stress vulnerability and impairs antidepressant responses following psychosocial stress.

Brain serotonin (5-HT) deficiency and exposure to psychosocial stress have both been implicated in the etiology of depression and anxiety disorders, but whether 5-HT deficiency influences susceptibility to depression- and anxiety-like phenotypes induced by psychosocial stress has not been formally established. Most clinically effective antidepressants increase the extracellular levels of 5-HT, and thus it has been hypothesized that antidepressant responses result from the reversal of endogenous 5-HT deficiency, but this hypothesis remains highly controversial. Here we evaluated the impact of brain 5-HT deficiency on stress susceptibility and antidepressant-like responses using tryptophan hydroxylase 2 knockin (Tph2KI) mice, which display 60-80% reductions in brain 5-HT.

Serotonin deficiency alters susceptibility to the long-term consequences of adverse early life experience.

Brain 5-HT deficiency has long been implicated in psychiatric disease, but the effects of 5-HT deficiency on stress susceptibility remain largely unknown. Early life stress (ELS) has been suggested to contribute to adult psychopathology, but efforts to study the long-term consequences of ELS have been limited by a lack of appropriate preclinical models. Here, we evaluated the effects of 5-HT deficiency on several long-term cellular, molecular, and behavioral responses of mice to a new model of ELS that combines early-life maternal separation (MS) of pups and postpartum learned helplessness (LH) training in dams.

Chronic fluoxetine increases extra-hippocampal neurogenesis in adult mice.

Background: Chronic treatment with antidepressants has been shown to enhance neurogenesis in the adult mammalian brain. Although this effect was initially reported to be restricted to the hippocampus, recent work has suggested that fluoxetine, a selective serotonin reuptake inhibitor, also promotes neurogenesis in the cortex. However, whether antidepressants target neural progenitor cells in other brain regions has not been examined.

The interaction of escitalopram and R-citalopram at the human serotonin transporter investigated in the mouse.

Rationale: Escitalopram appears to be a superior antidepressant to racemic citalopram. It has been hypothesized that binding of R-citalopram to the serotonin transporter (SERT) antagonizes escitalopram binding to and inhibition of the SERT, there by curtailing the elevation of extracellular 5-hydroxytryptamine (5-HTExt), and hence anti-depressant efficacy. Further, it has been suggested that a putative allosteric binding site is important for binding of escitalopram to the primary, orthosteric, site, and for R-citalopram's inhibition here of.

Sex differences in response to chronic mild stress and congenital serotonin deficiency.

Women exhibit a nearly twofold increased risk of developing depression and anxiety disorders when compared to men, a fact that has been hypothesized to result in part from increased stress susceptibility. Here, we used the tryptophan hydroxylase-2 R439H knock-in mouse (Tph2KI) and the chronic unpredictable mild stress (CMS) model to examine sex differences in response to congenital 5-HT deficiency and chronic stress. Our results demonstrate that female mice, but not 5-HT-deficient animals, exhibit significantly increased susceptibility to CMS-induced despair-like behavior in the forced swim test.

Congenital brain serotonin deficiency leads to reduced ethanol sensitivity and increased ethanol consumption in mice.

Serotonergic dysfunction has been hypothesized to play an important role in the pathophysiology of alcoholism. However, whether congenital serotonin (5-HT) deficiency leads to increased alcohol consumption or affects ethanol-related behaviors has not been established. Here, we use a transgenic mouse line that expresses a hypofunctional variant of the 5-HT synthesis enzyme, tryptophan hydroxylase 2, to examine the impact of 5-HT deficiency on responses to alcohol.

The effects of brain serotonin deficiency on behavioural disinhibition and anxiety-like behaviour following mild early life stress.

Aberrant serotonin (5-HT) signalling and exposure to early life stress have both been suggested to play a role in anxiety- and impulsivity-related behaviours. However, whether congenital 5-HT deficiency × early life stress interactions influence the development of anxiety- or impulsivity-like behaviour has not been established. Here, we examined the effects of early life maternal separation (MS) stress on anxiety-like behaviour and behavioural disinhibition, a type of impulsivity-like behaviour, in wild-type (WT) and tryptophan hydroxylase 2 (Tph2) knock-in (Tph2KI) mice, which exhibit ~60-80% reductions in the levels of brain 5-HT due to a R439H mutation in Tph2.

Cortical-amygdalar circuit dysfunction in a genetic mouse model of serotonin deficiency.

Although the majority of first-line antidepressants increase brain serotonin and rare polymorphisms in tryptophan hydroxlase-2 (Tph2), the rate-limiting enzyme in the brain serotonin synthesis pathway, have been identified in cohorts of subjects with major depressive disorder, the circuit level alterations that results from serotonergic hypofunction remain poorly understood. Here we use chronic multicircuit neurophysiological recordings to characterize functional interactions across cortical and limbic circuits in mice engineered to express a human loss-of-function depression allele Tph2-(R441H) [Tph2 knockin (Tph2KI)]. Our results show that Tph2KI mice exhibit increased intra-network synchrony within medial prefrontal cortex (mPFC) and basal amygdala (AMY) and increased inter-network synchrony between these two brain networks.

Chronic SSRI treatment exacerbates serotonin deficiency in humanized Tph2 mutant mice.

Selective serotonin reuptake inhibitors (SSRIs) are a major class of antidepressants that act by blocking inward transport of serotonin (5-HT) into presynaptic neurons mediated by the serotonin transporter (SERT). Both reuptake and ongoing synthesis are essential in supporting intraneuronal serotonin concentrations in serotonergic neurons. A rare mutation in tryptophan hydroxylase 2 (Tph2), the rate limiting enzyme for 5-HT synthesis, was identified in several patients with major depression, and knock-in mice expressing the analogous mutation (R439H Tph2 KI) show 80% reduction in 5-HT synthesis and tissue levels.

Pharmacological blockade of a β(2)AR-β-arrestin-1 signaling cascade prevents the accumulation of DNA damage in a behavioral stress model.

Chronic stress is known to have a profound negative impact on human health and has been suggested to influence a number of disease states. However, the mechanisms underlying the deleterious effects of stress remain largely unknown. Stress is known to promote the release of epinephrine, a catecholamine stress hormone that binds to β(2)-adrenergic receptors (β(2)ARs) with high affinity.

p75 neurotrophin receptor regulates glucose homeostasis and insulin sensitivity.

Insulin resistance is a key factor in the etiology of type 2 diabetes. Insulin-stimulated glucose uptake is mediated by the glucose transporter 4 (GLUT4), which is expressed mainly in skeletal muscle and adipose tissue. Insulin-stimulated translocation of GLUT4 from its intracellular compartment to the plasma membrane is regulated by small guanosine triphosphate hydrolases (GTPases) and is essential for the maintenance of normal glucose homeostasis.