Prolactin-mediated restraint of maternal aggression in lactation.

Aggressive behavior is rarely observed in virgin female mice but is specifically triggered in lactation where it facilitates protection of offspring. Recent studies demonstrated that the hypothalamic ventromedial nucleus (VMN) plays an important role in facilitating aggressive behavior in both sexes. Here, we demonstrate a role for the pituitary hormone, prolactin, acting through the prolactin receptor in the VMN to control the intensity of aggressive behavior exclusively during lactation. Prolactin receptor deletion from glutamatergic neurons or specifically from the VMN resulted in hyperaggressive lactating females, with a marked shift from intruder-directed investigative behavior to very high levels of aggressive behavior. Prolactin-sensitive neurons in the VMN project to a wide range of other hypothalamic and extrahypothalamic regions, including the medial preoptic area, paraventricular nucleus, and bed nucleus of the stria terminalis, all regions known to be part of a complex neuronal network controlling maternal behavior. Within this network, prolactin acts in the VMN to specifically restrain male-directed aggressive behavior in lactating females. This action in the VMN may complement the role of prolactin in other brain regions, by shifting the balance of maternal behaviors from defense-related activities to more pup-directed behaviors necessary for nurturing offspring.

Pretrauma risk factors and posttraumatic stress disorder symptoms following subsequent exposure: Multilevel and univariate meta-analytical approaches.

The endeavour to comprehend why certain individuals develop posttraumatic stress disorder (PTSD) symptoms subsequent to experiencing traumatic events, while others do not, underscores the paramount importance of pretraumatic risk factors. This meta-analysis summarises the extant results of studies assessing risk factors prior exposure and PTSD symptoms following an index event on the same participants. It includes 43 studies (N = 19,239) yielding 174 effect sizes of pretraumatic risk factors categories such as demographic factors, cognitive factors, personality traits, coping styles, psychopathology, psychophysiological and environmental factors, which were examined using a three-level meta-analysis. Additionally, univariate random-effects meta-analyses were performed to separately investigate individual risk factors reported in more than one study. The findings revealed significant, small and medium associations for all categories, except for demographic factors and coping styles, also highlighting that certain individual risk factor domains (i.e. previous mental disorders, negative emotionality, sleep complaints and PTSD symptoms) represent the strongest predictors for PTSD symptoms after subsequent exposure. Several moderators were also investigated for individual risk factors. Future research could benefit from considering the interplay of pretraumatic risk factors to draw a more complex picture of the aetiology and underlying mechanisms of PTSD symptoms.

Psychometric evaluation of the PCL-5: assessing validity, diagnostic utility, and bifactor structures.

Background: The changes DSM-5 brought to the diagnostic criteria for posttraumatic stress disorder (PTSD) resulted in revising the most widely used instrument in assessing PTSD, namely the Posttraumatic Checklist for DSM-5 (PCL-5).Objective: This study examined the psychometric properties of the Romanian version of the PCL-5, tested its diagnostic utility against the Structured Clinical Interview for DSM-5 (SCID-5), and investigated the latent structure of PTSD symptoms through correlated symptom models and bifactor modelling.Method: A total sample of 727 participants was used to test the psychometric properties and underlying structure of the PCL-5 and 101 individuals underwent clinical interviews using SCID-5. Receiver operating characteristic curve (ROC) analyses were performed to test the diagnostic utility of the PCL-5 and identify optimal cut-off scores based on Youden's J index. Confirmatory Factor Analyses (CFAs) and bifactor modelling were performed to investigate the latent structure of PTSD symptoms.Results: Estimates revealed that the PCL-5 is a valuable tool with acceptable diagnostic accuracy compared to SCID-5 diagnoses, indicating a cut-off score of >47. The CFAs provide empirical support for Anhedonia, Hybrid, and bifactor models. The findings are limited by using retrospective, self-report data and the high percentage of female participants.Conclusions: The PCL-5 is a psychometrically sound instrument that can be useful in making provisional diagnoses within community samples and improving trauma-informed practices.

This study offers an in-depth analysis of the Romanian version of the Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5), exploring its psychometric properties, diagnostic utility, and latent structure.An optimal cut-off score was identified for PTSD diagnosis using the SCID-5, providing essential insights into the diagnostic process and enhancing its utility in clinical assessments.Using bifactor modelling and other statistical methods, various PTSD models were compared to offer valuable guidance for future research, assessment, and interventions in this field.

The Role of Artificial Intelligence in Monitoring Inflammatory Bowel Disease-The Future Is Now.

Crohn's disease and ulcerative colitis remain debilitating disorders, characterized by progressive bowel damage and possible lethal complications. The growing number of applications for artificial intelligence in gastrointestinal endoscopy has already shown great potential, especially in the field of neoplastic and pre-neoplastic lesion detection and characterization, and is currently under evaluation in the field of inflammatory bowel disease management. The application of artificial intelligence in inflammatory bowel diseases can range from genomic dataset analysis and risk prediction model construction to the disease grading severity and assessment of the response to treatment using machine learning. We aimed to assess the current and future role of artificial intelligence in assessing the key outcomes in inflammatory bowel disease patients: endoscopic activity, mucosal healing, response to treatment, and neoplasia surveillance.

The structure of PTSD. Development of the Post Traumatic Symptom scale from a clinician-based perspective.

Background: Nations marked by a Marxist-Leninist ideology have suffered greatly due to a culture of abuse emphasized by the absolute absence of psychology, thus contributing to a diminished ability in recognizing the consequences of traumatic experiences. Objective: To improve the assessment of the presence and severity of posttraumatic stress disorder (PTSD) in such a cultural context, our paper aimed at developing an alternative self-report measure for PTSD - the Post Traumatic Symptom Scale (PTSs), developed by clinicians with wide relevant expertise, based on the natural language people use to describe its subjective experience. This research used multiple samples consistent with the corresponding objectives. Mokken Scale Analysis and the Classical Test Theory were both employed. The proposed scale was tested against five competing PTSD models, whilst also investigating the symptoms' clusters in two different samples by using, to our knowledge, a network analysis approach for the first time. Method: The results indicated excellent psychometric properties regarding internal consistency and temporal reliability, as well as convergent and discriminant validity. The results of MSA showed that the scale fully conforms to the assumptions of the monotone homogeneity model, interpreted as positive evidence for its use in clinical purposes. The factor analyses pointed that the newer models outperformed the standard DSM-5 model, with bifactor models displaying better fit indexes than second-order models. Finally, a distinct pattern of symptom activation in the high-risk group (i.e. first-responders) was found, bringing support for symptoms overlapping between PTSD and affective disorders, thus reinforcing the idea of bridge symptoms which has significant clinical implications. Results: This study presents an alternative sound instrument for measuring PTSD symptomatology focused on how people naturally describe their subjective experiences. Theoretical and practical implications are discussed alongside limitations. HIGHLIGHTS: The construction of PTSs encompasses cultural trauma and one's subjective experience.PTSs was tested against the five major competing models of PTSD.Network analyses suggest different patterns in a student sample vs. a first-responders one, with the accent on the negative alterations in cognitions and mood (NACM) model.

Role of serotonin in body weight, insulin secretion and glycaemic control.

Obesity and type 2 diabetes are key healthcare challenges of the 21st century. Subsequent to its discovery in 1948, serotonin (5-hydroxytryptamine; 5-HT) has emerged as a principal modulator of energy homeostasis and body weight, prompting it to be a target of weight loss medications (eg, fenfluramine, D-fenfluramine, fenfluramine-phentermine and sibutramine). The potential risk of off-target effects led to these medications being withdrawn from clinical use and spurred drug discovery into 5-HT receptor selective ligands. The serotonin 2C receptor (5-HT2C R) is the primary receptor through which 5-HT impacts feeding and body weight and 5-HT2C R agonist lorcaserin was released for obesity treatment in 2012. Obese patients with type 2 diabetes prescribed medications that produce weight loss commonly observe improvements in type 2 diabetes. However, recent research has provided compelling evidence that 5-HT2C R agonists produce effects on blood glucose and insulin sensitivity independent of weight loss. As such, neuroactive 5-HT2C R agonists are a potential new category of type 2 diabetes medications. 5-HT is also expressed within pancreatic ß cells, is co-released with insulin and may have a role in modulating insulin secretion. This review highlights the latest advances in the function of 5-HT in body weight, insulin release and glycaemic control.

The Prolactin Family of Hormones as Regulators of Maternal Mood and Behavior.

Transition into motherhood involves profound physiological and behavioral adaptations that ensure the healthy development of offspring while maintaining maternal health. Dynamic fluctuations in key hormones during pregnancy and lactation induce these maternal adaptations by acting on neural circuits in the brain. Amongst these hormonal changes, lactogenic hormones (e.g., prolactin and its pregnancy-specific homolog, placental lactogen) are important regulators of these processes, and their receptors are located in key brain regions controlling emotional behaviors and maternal responses. With pregnancy and lactation also being associated with a marked elevation in the risk of developing mood disorders, it is important to understand how hormones are normally regulating mood and behavior during this time. It seems likely that pathological changes in mood could result from aberrant expression of these hormone-induced behavioral responses. Maternal mental health problems during pregnancy and the postpartum period represent a major barrier in developing healthy mother-infant interactions which are crucial for the child's development. In this review, we will examine the role lactogenic hormones play in driving a range of specific maternal behaviors, including motivation, protectiveness, and mother-pup interactions. Understanding how these hormones collectively act in a mother's brain to promote nurturing behaviors toward offspring will ultimately assist in treatment development and contribute to safeguarding a successful pregnancy.

Acute effects of prolactin on hypothalamic prolactin receptor expressing neurones in the mouse.

In addition to its critical role in lactation, the anterior pituitary hormone prolactin also influences a broad range of other physiological processes. In particular, widespread expression of prolactin receptor (Prlr) in the brain has highlighted pleiotropic roles for prolactin in regulating neuronal function, including maternal behaviour, reproduction and energy balance. Research into the central actions of prolactin has predominately focused on effects on gene transcription via the canonical JAK2/STAT5; however, it is evident that prolactin can exert rapid actions to stimulate activity in specific populations of neurones. We aimed to investigate how widespread these rapid actions of prolactin are in regions of the brain with large populations of prolactin-sensitive neurones, and whether physiological state alters these responses. Using transgenic mice where the Cre-dependent calcium indicator, GCaMP6f, was conditionally expressed in cells expressing the long form of the Prlr, we monitored changes in levels of intracellular calcium ([Ca2+ ]i ) in ex vivo brain slice preparations as a surrogate marker of cellular activity. Here, we surveyed hypothalamic regions implicated in the diverse physiological functions of prolactin such as the arcuate (ARC) and paraventricular nuclei of the hypothalamus (PVN), as well as the medial preoptic area (MPOA). We observed that, in the ARC of males and in both virgin and lactating females, prolactin can exert rapid actions to stimulate neuronal activity in the majority of Prlr-expressing neurones. In the PVN and MPOA, we found a smaller subset of cells that rapidly respond to prolactin. In these brain regions, the effects we detected ranged from rapid or sustained increases in [Ca2+ ]i to inhibitory effects, indicating a heterogeneous nature of these Prlr-expressing populations. These results enhance our understanding of mechanisms by which prolactin acts on hypothalamic neurones and provide insights into how prolactin might influence neuronal circuits in the mouse brain.

Neurochemical Characterization of Brainstem Pro-Opiomelanocortin Cells.

Genetic research has revealed pro-opiomelanocortin (POMC) to be a fundamental regulator of energy balance and body weight in mammals. Within the brain, POMC is primarily expressed in the arcuate nucleus of the hypothalamus (ARC), while a smaller population exists in the brainstem nucleus of the solitary tract (POMCNTS). We performed a neurochemical characterization of this understudied population of POMC cells using transgenic mice expressing green fluorescent protein (eGFP) under the control of a POMC promoter/enhancer (PomceGFP). Expression of endogenous Pomc mRNA in the nucleus of the solitary tract (NTS) PomceGFP cells was confirmed using fluorescence-activating cell sorting (FACS) followed by quantitative PCR. In situ hybridization histochemistry of endogenous Pomc mRNA and immunohistochemical analysis of eGFP revealed that POMC is primarily localized within the caudal NTS. Neurochemical analysis indicated that POMCNTS is not co-expressed with tyrosine hydroxylase (TH), glucagon-like peptide 1 (GLP-1), cholecystokinin (CCK), brain-derived neurotrophic factor (BDNF), nesfatin, nitric oxide synthase 1 (nNOS), seipin, or choline acetyltransferase (ChAT) cells, whereas 100% of POMCNTS is co-expressed with transcription factor paired-like homeobox2b (Phox2b). We observed that 20% of POMCNTS cells express receptors for adipocyte hormone leptin (LepRbs) using a PomceGFP:LepRbCre:tdTOM double-reporter line. Elevations in endogenous or exogenous leptin levels increased the in vivo activity (c-FOS) of a small subset of POMCNTS cells. Using ex vivo slice electrophysiology, we observed that this effect of leptin on POMCNTS cell activity is postsynaptic. These findings reveal that a subset of POMCNTS cells are responsive to both changes in energy status and the adipocyte hormone leptin, findings of relevance to the neurobiology of obesity.

Nucleus of the Solitary Tract Serotonin 5-HT2C Receptors Modulate Food Intake.

To meet the challenge to human health posed by obesity, a better understanding of the regulation of feeding is essential. Medications targeting 5-hydroxytryptamine (5-HT; serotonin) 2C receptors (htr2c; 5-HT2CR) improve obesity. Here we probed the functional significance of 5-HT2CRs specifically within the brainstem nucleus of the solitary tract (5-HT2CRNTS) in feeding behavior. Selective activation of 5-HT2CRNTS decreased feeding and was sufficient to mediate acute food intake reductions elicited by the 5-HT2CR agonist obesity medication lorcaserin. Similar to pro-opiomelanocortin neurons expressed within the hypothalamic arcuate nucleus (POMCARC), a subset of POMCNTS neurons co-expressed 5-HT2CRs and were activated by 5-HT2CR agonists. Knockdown of POMCNTS prevented the acute appetite-suppressive effect of lorcaserin, whereas POMCARC knockdown prevented the full anorectic effect. These data identify 5-HT2CRNTS as a sufficient subpopulation of 5-HT2CRs in reducing food intake when activated and reveal that 5-HT2CR agonist obesity medications require POMC within the NTS and ARC to reduce food intake.

Activation of Ventral Tegmental Area 5-HT2C Receptors Reduces Incentive Motivation.

Obesity is primarily due to food intake in excess of the body's energetic requirements, intake that is not only associated with hunger but also the incentive value of food. The 5-hydroxytryptamine 2C receptor (5-HT2CR) is a target for the treatment of human obesity. Mechanistically, 5-HT2CRs are positioned to influence both homeostatic feeding circuits within the hypothalamus and reward circuits within the ventral tegmental area (VTA). Here we investigated the role of 5-HT2CRs in incentive motivation using a mathematical model of progressive ratio (PR) responding in mice. We found that the 5-HT2CR agonist lorcaserin significantly reduced both ad libitum chow intake and PR responding for chocolate pellets and increased c-fos expression in VTA 5-HT2CR expressing γ-aminobutyric acid (GABA) neurons, but not 5-HT2CR expressing dopamine (DA) neurons. We next adopted a chemogenetic approach using a 5-HT2CRCRE line to clarify the function of subset of 5-HT2C receptor expressing VTA neurons in the modulation of appetite and food-motivated behavior. Activation of VTA 5-HT2C receptor expressing neurons significantly reduced ad libitum chow intake, operant responding for chocolate pellets, and the incentive value of food. In contrast, chemogenetic inhibition of VTA 5-HT2C receptor expressing neurons had no effect on the feeding behavior. These results indicate that activation of the subpopulation of 5-HT2CR neurons within the VTA is sufficient to significantly reduce homeostatic feeding and effort-based intake of palatable food, and that this subset has an inhibitory role in motivational processes. These findings are relevant to the treatment of obesity.

Lorcaserin improves glycemic control via a melanocortin neurocircuit.

OBJECTIVE: The increasing prevalence of type 2 diabetes (T2D) and associated morbidity and mortality emphasizes the need for a more complete understanding of the mechanisms mediating glucose homeostasis to accelerate the identification of new medications. Recent reports indicate that the obesity medication lorcaserin, a 5-hydroxytryptamine (5-HT, serotonin) 2C receptor (5-HT2CR) agonist, improves glycemic control in association with weight loss in obese patients with T2D. Here we evaluate whether lorcaserin has an effect on glycemia without body weight loss and how this effect is achieved. METHODS: Murine models of common and genetic T2D were utilized to probe the direct effect of lorcaserin on glycemic control. RESULTS: Lorcaserin dose-dependently improves glycemic control in mouse models of T2D in the absence of reductions in food intake or body weight. Examining the mechanism of this effect, we reveal a necessary and sufficient neurochemical mediator of lorcaserin's glucoregulatory effects, brain pro-opiomelanocortin (POMC) peptides. To clarify further lorcaserin's therapeutic brain circuit, we examined the receptor target of POMC peptides. We demonstrate that lorcaserin requires functional melanocortin4 receptors on cholinergic preganglionic neurons (MC4RChAT) to exert its effects on glucose homeostasis. In contrast, MC4RChAT signaling did not impact lorcaserin's effects on feeding, indicating a divergence in the neurocircuitry underpinning lorcaserin's therapeutic glycemic and anorectic effects. Hyperinsulinemic-euglycemic clamp studies reveal that lorcaserin reduces hepatic glucose production, increases glucose disposal and improves insulin sensitivity. CONCLUSIONS: These data suggest that lorcaserin's action within the brain represents a mechanistically novel treatment for T2D: findings of significance to a prevalent global disease.

Sex difference in physical activity, energy expenditure and obesity driven by a subpopulation of hypothalamic POMC neurons.

OBJECTIVE: Obesity is one of the primary healthcare challenges of the 21st century. Signals relaying information regarding energy needs are integrated within the brain to influence body weight. Central among these integration nodes are the brain pro-opiomelanocortin (POMC) peptides, perturbations of which disrupt energy balance and promote severe obesity. However, POMC neurons are neurochemically diverse and the crucial source of POMC peptides that regulate energy homeostasis and body weight remains to be fully clarified. METHODS: Given that a 5-hydroxytryptamine 2c receptor (5-HT2CR) agonist is a current obesity medication and 5-HT2CR agonist's effects on appetite are primarily mediated via POMC neurons, we hypothesized that a critical source of POMC regulating food intake and body weight is specifically synthesized in cells containing 5-HT2CRs. To exclusively manipulate Pomc synthesis only within 5-HT2CR containing cells, we generated a novel 5-HT 2C R (CRE) mouse line and intercrossed it with Cre recombinase-dependent and hypothalamic specific reactivatable Pomc (NEO) mice to restrict Pomc synthesis to the subset of hypothalamic cells containing 5-HT2CRs. This provided a means to clarify the specific contribution of a defined subgroup of POMC peptides in energy balance and body weight. RESULTS: Here we transform genetically programed obese and hyperinsulinemic male mice lacking hypothalamic Pomc with increased appetite, reduced physical activity and compromised brown adipose tissue (BAT) into lean, healthy mice via targeted restoration of Pomc function only within 5-HT2CR expressing cells. Remarkably, the same metabolic transformation does not occur in females, who despite corrected feeding behavior and normalized insulin levels remain physically inactive, have lower energy expenditure, compromised BAT and develop obesity. CONCLUSIONS: These data provide support for the functional heterogeneity of hypothalamic POMC neurons, revealing that Pomc expression within 5-HT2CR expressing neurons is sufficient to regulate energy intake and insulin sensitivity in male and female mice. However, an unexpected sex difference in the function of this subset of POMC neurons was identified with regard to energy expenditure. We reveal that a large sex difference in physical activity, energy expenditure and the development of obesity is driven by this subpopulation, which constitutes approximately 40% of all POMC neurons in the hypothalamic arcuate nucleus. This may have broad implications for strategies utilized to combat obesity, which at present largely ignore the sex of the obese individual.

Systematic screen for mutants resistant to TORC1 inhibition in fission yeast reveals genes involved in cellular ageing and growth.

Target of rapamycin complex 1 (TORC1), which controls growth in response to nutrients, promotes ageing in multiple organisms. The fission yeast Schizosaccharomyces pombe emerges as a valuable genetic model system to study TORC1 function and cellular ageing. Here we exploited the combinatorial action of rapamycin and caffeine, which inhibit fission yeast growth in a TORC1-dependent manner. We screened a deletion library, comprising ∼84% of all non-essential fission yeast genes, for drug-resistant mutants. This screen identified 33 genes encoding functions such as transcription, kinases, mitochondrial respiration, biosynthesis, intra-cellular trafficking, and stress response. Among the corresponding mutants, 5 showed shortened and 21 showed increased maximal chronological lifespans; 15 of the latter mutants showed no further lifespan increase with rapamycin and might thus represent key targets downstream of TORC1. We pursued the long-lived sck2 mutant with additional functional analyses, revealing that the Sck2p kinase functions within the TORC1 network and is required for normal cell growth, global protein translation, and ribosomal S6 protein phosphorylation in a nutrient-dependent manner. Notably, slow cell growth was associated with all long-lived mutants while oxidative-stress resistance was not.