Behavioral Phenotypes Research Articles

Behavioral and neural correlates of diverse conditioned fear responses in male and female rats

Pavlovian fear conditioning is a widely used tool that models associative learning in rodents. For decades the field has used predominantly male rodents and focused on a sole conditioned fear response: freezing. However, recent work from our lab and others has identified darting as a female-biased conditioned response, characterized by an escape-like movement across a fear conditioning chamber. It is also accompanied by a behavioral phenotype: Darters reliably show decreased freezing compared to Non-darters and males and reach higher velocities in response to the foot shock (“shock response”). However, the relationship between shock response and conditioned darting is not known. This study investigated if this link is due to differences in general processing of aversive stimuli between Darters, Non-darters and males. Across a variety of modalities, including corticosterone measures, the acoustic startle test, and sensitivity to thermal pain, Darters were found not to be more reactive or sensitive to aversive stimuli, and, in some cases, they appear less reactive to Non-darters and males. Analyses of cFos activity in regions involved in pain and fear processing following fear conditioning identified discrete patterns of expression among Darters, Non-darters, and males exposed to low and high intensity foot shocks. The results from these studies further our understanding of the differences between Darters, Non-darters and males and highlight the importance of studying individual differences in fear conditioning as indicators of fear state.

A supergene affects androgen concentrations during early development in a bird with alternative reproductive morphs

Species with alternative reproductive tactics typically show pronounced phenotypic variation between and within sexes. In some species, this variation culminates in discrete reproductive morphs that are genetically determined, facilitating studies on how genetic variation translates into phenotypic variation. In ruffs (Calidris pugnax), an autosomal inversion polymorphism underlies three reproductive morphs (Independents, Satellites and Faeders), which differ in circulating steroid concentrations in adults. Yet, it remains unknown whether morph differences in steroid concentrations already arise before adulthood. We examined variation in circulating testosterone, androstenedione and progesterone concentrations between morphs and sexes in ruff chicks and juveniles and compared the differences to those in adults. Since measured hormone concentrations only provide momentary states and show high within- and between-individual variation, we took repeated measurements to compare means, variances and skewness between groups. We found clear differences between morphs but not the sexes in early life. Between morphs, androgen concentrations in young ruffs differed in variance and skewness, but not in their means. For testosterone, Independents had a higher variance than Satellites/Faeders, whereas for androstenedione, we observed the opposite pattern. For progesterone, we did not detect clear differences between groups. Skewness values mirrored differences in morph variances. Compared to adults, premature ruffs had lower androgen concentrations. In both life stages, we detected morph-specific associations between androgen concentrations: androstenedione concentrations increased with testosterone concentrations more in Satellites/Faeders than in Independents. These observed morph differences during early life are consistent with a supergene-mediated regulation of androgen variation that underlies the diversification of adult behavioural phenotypes.

The Effect of Donepezil Hydrochloride in the Twitcher Mouse Model of Krabbe Disease.

Krabbe disease (KD) is a rare demyelinating disorder characterized by demyelination caused by mutations in the GALC gene, resulting in toxic accumulation of psychosine. Psychosine has been identified as detrimental to oligodendrocytes, leading to demyelination through diverse hypothesized pathways. Reducing demyelination is essential to maintain neurological function in KD; however, therapeutic interventions are currently limited. Acetylcholinesterase inhibitors (AChEi) are commonly used for symptomatic management of Alzheimer's Disease and are suggested to have potential disease-modifying effects, including regulating myelin state. In particular, donepezil, an AChEi, has demonstrated promising effects in cellular and animal models, including promotion of the expression of myelin-related genes and reduction of glial cell reactivity. This drug also acts as an agonist for sigma-1 receptors (Sig-1R), which are implicated in demyelination diseases. In the context of drug repurposing, here, we demonstrate that administration of donepezil has protective effects in the twitcher mouse model of KD. We provide data showing that donepezil preserves myelin and reduces glial cell reactivity in the brains of twitcher mice. Moreover, donepezil also improves behavioral phenotypes and increases lifespan in twitcher animals. These findings suggest that donepezil, with its dual activity as an AChE inhibitor and Sig-1R agonist, may hold promise as a therapeutic candidate for demyelinating diseases, including KD.

Characterization of Brain Abnormalities in Lactational Neurodevelopmental Poly I:C Rat Model of Schizophrenia and Depression Using Machine-Learning and Quantitative MRI.

A recent neurodevelopmental rat model, utilizing lactational exposure to polyriboinosinic-polyribocytidilic acid (Poly I:C) leads to mimics of behavioral phenotypes resembling schizophrenia-like symptoms in male offspring and depression-like symptoms in female offspring. To identify mechanisms of neuronal abnormalities in lactational Poly I:C offspring using quantitative MRI (qMRI) tools. Prospective. Twenty Poly I:C rats and 20 healthy control rats, age 130 postnatal day. 7 T. Multiflip-angle FLASH protocol for T1 mapping; multi-echo spin-echo T2-mapping protocol; echo planar imaging protocol for diffusion tensor imaging. Nursing dams were injected with the viral mimic Poly I:C or saline (control group). In adulthood, quantitative maps of T1, T2, proton density, and five diffusion metrics were generated for the offsprings. Seven regions of interest (ROIs) were segmented, followed by extracting 10 quantitative features for each ROI. Random forest machine learning (ML) tool was employed to identify MRI markers of disease and classify Poly I:C rats from healthy controls based on quantitative features. Poly I:C rats were identified from controls with an accuracy of 82.5 ± 25.9% for females and 85.0 ± 24.0% for males. Poly I:C females exhibited differences mainly in diffusion-derived parameters in the thalamus and the medial prefrontal cortex (MPFC), while males displayed changes primarily in diffusion-derived parameters in the corpus callosum and MPFC. qMRI shows potential for identifying sex-specific brain abnormalities in the Poly I:C model of neurodevelopmental disorders. NA TECHNICAL EFFICACY: Stage 2.

A self‐cooling self‐humidifying mosquito carrier backpack for transporting live adult mosquitoes on foot over long distances under challenging field conditions

AbstractIt is often necessary to use motorised transport to move live mosquitoes from distant field collection points into a central insectary, so that their behavioural and/or physiological phenotypes can be assessed under carefully controlled conditions. However, a survey of heritable insecticide susceptibility traits among wild‐caught Anopheles arabiensis mosquitoes, collected across an extensive study area composed largely of wilderness in southern Tanzania, necessitated that live mosquitoes were carried on foot over distances up to 25 km per day because most of the area was impassable by car, motorcycle or even bicycle during the rains. A self‐cooling, self‐humidifying carrier backpack was therefore developed that allows live adult mosquito specimens to be transported across rugged miombo woodland and floodplain terrain throughout the year. This wettable backpack was fabricated from stitched Tanzanian kitenge cotton fabric and polyvinyl chloride–coated fibreglass netting that allows easy circulation of air in and out. An outer cover flap made of cotton towelling embedded inside a kitenge envelope overhangs the fibreglass netting upper body of the bag, to protect mosquitoes from direct sunlight, and can be soaked with water to maintain low temperature and high humidity inside. Mean survival of insectary‐reared female An. arabiensis transported through nine different mobile camps inside the 509 km2 Ifakara‐Lupiro‐Mang'ula wildlife management area (ILUMA WMA), over up to 143 km and 25 days, was statistically indistinguishable from those left in the field insectary over the same period. Although considerable variance of survival was observed between different batches of mosquitoes from the insectary and between individual cups of mosquitoes, the different levels and positions inside the backpack had no influence on this outcome. Temperature and humidity inside the backpack were maintained at standard insectary conditions throughout, despite much more extreme conditions immediately outside. When the backpack was used to transport wild An. arabiensis and Anopheles quadriannulatus across a much larger study area of >4000 km2, encompassing the ILUMA WMA, some nearby villages and adjacent parts of Nyerere National Park (NNP), it achieved a mean survival rate of 58.2% (95% confidence interval 47.5–68.2). Encouragingly, no difference in survival was observed between ILUMA WMA and NNP even though transport back from NNP involves much longer distances, sometimes involving lengthy journeys by car or boat. Overall, this mosquito carrier backpack prototype appears to represent a viable and effective method for transporting live wild‐caught mosquitoes on foot across otherwise impassable terrain under challenging weather conditions with minimal detrimental impact on their survival.

Timing of Maternal Stress Differentially Affects Immune and Stress Phenotypes in Progeny

Maternal stress during gestation may affect the development and responsiveness of the hypothalamic–pituitary–adrenal axis (HPA) and immune system in the progeny. Stressor type, duration and gestational stage at which the stressor occurs may all influence the short and long-term effects on the future progeny. The present study advances the characterization of the timing of gestational stress on the stress responsiveness and immune and behavioral phenotypes of the progeny. First, parity sows were hand-fed hydrocortisone acetate (stressed) or placebo (controls) during mid or late gestation. Colostrum and cord blood were collected. Blood samples were obtained from a subset of piglets (n = 36) born to these sows during lactation, pre- and post-weaning, and during an ACTH challenge. Stress and immune measures were assessed. Piglets born to sows stressed during mid-gestation had reduced measures of humoral immunity, including immunoglobulins and interleukin-4. Conversely, piglets born to late-stressed sows exhibited a delayed or dampened stress response to weaning and an ACTH challenge. They also had a skewed pro-inflammatory phenotype, as evidenced by increased interleukin-17 and tumor necrosis factor-α. Overall, these data suggest that the stage of gestation at which gestational stress occurs has differential effects on the HPA axis and immune development of the progeny, resulting in differential stress responsiveness and immune and behavioral phenotypes.

Associations between genotype, phenotype and behaviours measured by the Rett syndrome behaviour questionnaire in Rett syndrome

IntroductionRett syndrome (RTT) is a rare neurodevelopmental disorder with developmental impairments, comorbidities, and abnormal behaviours such as hand stereotypies and emotional features. The Rett Syndrome Behaviour Questionnaire (RSBQ) was developed to describe the behavioural and emotional features of RTT. Little is known how RSBQ scores are associated with genetic and clinical characteristics in RTT. This study investigated relationships between genotype, age, walking, hand function, sleep, and RSBQ total and subscale scores in RTT.MethodsThis is a cross-sectional analysis of data collected in the Australian Rett Syndrome Database and the International Rett Syndrome Phenotype Database. Parent caregivers completed the RSBQ and Sleep Disturbance Scale for Children [subscales for disorders of initiating and maintaining sleep (DIMS), disorders of excessive somnolence (DOES)], and provided information on age, variant type, functional abilities (mobility, hand function), seizure frequency and gastrointestinal problems. Associations between the RSBQ scores and the independent variables were modelled using linear regression.ResultsData were available for 365 individuals with RTT [median (range) age 17.8 (2.9–51.9) years, 2 males]. Compared to adults, 2- to 12-year-old children had higher mean Total, Night-time Behaviour and Fear/Anxiety scores. Compared to individuals with a C-terminal deletion, individuals with the p.Arg255* variant had higher mean Total and Night-time Behaviours scores, whereas the p.Arg294* variant had higher mean Mood scores. Individuals with intermediate mobility and hand function abilities had a higher mean Total score. Total RSBQ and subscale scores were similar across categories for seizures, constipation, and reflux, but were higher with abnormal DIMS and abnormal DOES scores.ConclusionExcept for associations with sleep, the RSBQ measures the behavioural phenotype rather than clinical severity in RTT, as traditionally conceptualised in terms of functional abilities and comorbidities. When designing clinical trials, the RSBQ needs to be complemented by other outcome measures to assess specific core functions and associated comorbidities in RTT.

The Influence of the Estrous Cycle on Neuropeptide S Receptor-Mediated Behaviors.

The Neuropeptide S receptor (NPSR) has been identified as a potential therapeutic target for anxiety and post-traumatic stress disorder. Central administration of Neuropeptide S (NPS) in male mice produces anxiolytic-like effects, hyperlocomotion, and memory enhancement. Currently, the literature is limited in the number of studies investigating the effects of NPS in female test subjects despite females facing a higher prevalence of anxiety-related pathology, as well as greater risk for adverse effects while taking psychoactive drugs. Moreover, no previous studies have considered the influence of estrous cycle on the effects of NPS. The current study investigates whether NPS-mediated behavioral phenotypes seen in males translate to females, and whether they are affected by estrous cycle stage. Female C57BL/6NCr mice were intracerebroventricularly (ICV) cannulated and underwent behavioral paradigms to test locomotion, anxiety, and memory. Estrous cycle stage was determined through examination of vaginal cytology. Our results provide evidence that NPS-mediated behaviors are influenced by the estrous cycle. Administration of NPS decreased anxiety-like behaviors more robustly when the female mice were in high estrogen stages of the estrous cycle. Therefore, the desired anxiolytic-like effects of targeting the NPSR are intact in female mice. However, these effects may to be influenced by the stage of the estrous cycle. The NPSR remains a strong potential drug target for new anxiolytic compounds and based on our initial observations further studies exploring the interaction of estrous cycle and the NPS-system are warranted. Significance Statement The neuropeptide S (NPS) receptor has been identified as a potential target for treating anxiety, a condition that is most prevalent in females. Therefore, the potential interaction of estrous cycle with the NPS-system described in the current study is an important first step in understanding the function of the NPS-system in females.

AST-120 Protects Cognitive and Emotional Impairment in Chronic Kidney Disease Induced by 5/6 Nephrectomy

Background: Uremic toxins resulting from chronic kidney disease (CKD) can cause cognitive and emotional disorders, as well as cardiovascular diseases. Indoxyl sulfate (IS) and p-cresol are notable uremic toxins found in patients with CKD. However, few studies have investigated whether reducing uremic toxins can alleviate cognitive and emotional disorders associated with CKD. Methods: We studied the effects of AST-120, which lowers IS levels, through behavioral tests, local field potentials, field excitatory postsynaptic potentials, and histological experiments in a 5/6 nephrectomy CKD model. Results: We confirmed AST-120’s effectiveness in CKD by measuring serum creatinine, blood urea nitrogen, and IS levels and performing renal tissue staining. Behavioral phenotypes indicated an alleviation of cognitive and anxiety disorders following AST-120 treatment in CKD-induced rats, which was further validated through local field potentials and field excitatory postsynaptic potential recordings. Double immunofluorescence staining for aquaporin-4 and glial fibrillary acidic protein in the hippocampus of CKD rats treated with AST-120 showed reduced coexpression. Conclusions: Our findings demonstrate the potential therapeutic effects of AST-120 in lowering IS levels and improving cognitive and emotional impairments associated with CKD.

Frequency and Longitudinal Course of Behavioral and Neuropsychiatric Symptoms in Participants With Genetic Frontotemporal Dementia.

Behavioral and neuropsychiatric symptoms are frequent in patients with genetic frontotemporal dementia (FTD). We aimed to describe behavioral and neuropsychiatric phenotypes in genetic FTD, quantify their temporal association, and investigate their regional association with brain atrophy. We analyzed data of pathogenic variant carriers in the chromosome 9 open reading frame 72 (c9orf72), progranulin (GRN), or microtubule-associated protein tau (MAPT) gene from the Genetic Frontotemporal dementia Initiative cohort study that enrolls both symptomatic pathogenic variant carriers and first-degree relatives of known carriers. Principal component analysis was performed to identify behavioral and neuropsychiatric clusters that were compared with respect to frequency and severity between groups. Associations between neuropsychiatric clusters and MRI-assessed atrophy were determined using voxel-based morphometry. We applied linear mixed effects and generalized linear mixed effects models to assess the longitudinal course of symptoms. A total of 522 participants were included: 221 c9orf72 (138 presymptomatic), 213 GRN (157 presymptomatic), and 88 MAPT (62 presymptomatic) pathogenic variant carriers. Principal component analysis revealed 5 phenotypic clusters (67.6% of variance), labeled diverse behavioral, affective, psychotic, euphoric/hypersexual, and tactile hallucinations phenotype. In participants presenting behavioral or neuropsychiatric symptoms, affective symptoms were most frequent across groups (83.6%-88.1%), followed by diverse behavioral symptoms (68.4%-77.9%). In c9orf72 and GRN pathogenic variant carriers, psychotic symptoms (32.0% and 19.4%, respectively) were more frequent than euphoric/hypersexual symptoms (28.7% and 14.2%, respectively), which was the other way around in MAPT pathogenic variant carriers (28.6% and 23.8%). Although diverse behavioral symptoms were associated with gray and white matter frontotemporal atrophy, only a small atrophy cluster in the right thalamus was associated with psychotic symptoms. Euphoric/hypersexual symptoms were associated with atrophy in mesial temporal lobes, basal forebrain structures, and the striatum (p < 0.05). Estimated time to symptom onset, genetic group, education, and sex influenced behavioral and neuropsychiatric symptoms (p < 0.05). Particularly, in c9orf72 pathogenic variant carriers, psychotic symptoms may be starting decades before recognition of onset of illness. We identified multiple clusters of behavioral and neuropsychiatric symptoms in participants with genetic FTD that relate to distinct cerebral atrophy patterns. Their severity depends on time, affected gene, sex, and education. These clinical-genetic associations can guide diagnostic evaluations and the design of clinical trials for new disease-modifying and preventive treatments.

Deep phenotyping reveals CRH and FKBP51-dependent behavioral profiles following chronic social stress exposure in male mice.

The co-chaperone FKBP51, encoded by FKBP5 gene, is recognized as a psychiatric risk factor for anxiety and depressive disorders due to its crucial role in the stress response. Another key modulator in stress response regulation is the corticotropin releasing hormone (CRH), which is co-expressed with FKBP51 in many stress-relevant brain-regions and cell-types. Together, they intricately influence the balance of the hypothalamic-pituitary-adrenal (HPA) axis, one of the primary stress response systems. Previous research underscores the potential moderating effects these genes have on the regulation of the stressful life events towards the vulnerability of major depressive disorder (MDD). However, the specific function of FKBP51 in CRH-expressing neurons remains largely unexplored. Here, through deep behavioral phenotyping, we reveal heightened stress effects in mice lacking FKBP51 in CRH co-expressing neurons (CRHFKBP5-/-), particularly evident in social contexts. Our findings highlight the importance of considering cell-type specificity and context in comprehending stress responses and advocate for the utilization of machine-learning-driven phenotyping of mouse models. By elucidating these intricacies, we lay down the groundwork for personalized interventions aimed at enhancing stress resilience and individual well-being.

Brivaracetam and rufinamide combination increased seizure threshold and improved neurobehavioral deficits in corneal kindling model of epilepsy.

Besides seizures, a myriad of overlapping neuropsychiatric and cognitive comorbidities occur in patients with epilepsy, which further debilitates their quality of life. This study provides an in-depth characterization of the impact of brivaracetam and rufinamide individually and in combination at 10 and 20 mg/kg doses, respectively, on corneal kindling-induced generalized seizures and behavioral alterations. Furthermore, observed convulsive frequency and behavioral changes were correlated to post-kindling-induced changes in the activity of markers of oxidative stress. Adult C57BL/6 mice were kindled via twice-daily transcorneal 50-Hz electrical stimulations (3 mA) for 3 s for 12 days until animals reached a fully kindled state. After the kindling procedure, animals were tested using a set of behavioral tests, and neurochemical alterations were assessed. Corneal-kindled animals exhibited intense generalized convulsions, altered behavioral phenotypes typified by positive symptoms (hyperlocomotion), negative symptoms (anxiety and anhedonia), and deficits in semantic and working memory. BRV 10 + RFM 20 dual regime increased convulsive threshold and propensity toward the start of stage 4-5 seizures and improved phenotypical deficits, that is, anxiety, depression, and memory impairments. Moreover, this combination therapy mitigated kindling-induced redox impairments as evidenced by reduced malondialdehyde and acetylcholinesterase levels and increased glutathione antioxidant activity in the brain of animals subjected to repetitive brain insult. Based on our outcomes, this dual therapy provides supporting evidence in alleviating epilepsy-induced neurobehavioral comorbidities and changes in redox homeostasis.

Dog10K: an integrated Dog10K database summarizing canine multi-omics.

The diversity observed in canine breed phenotypes, together with their risk for heritabily disorders of relevance to dogs and humans, makes the species an ideal subject for studies aimed at understanding the genetic basis of complex traits and human biomedical models. Dog10K is an ongoing international collaboration that aims to uncover the genetic basis of phenotypic diversity, disease, behavior, and domestication history of dogs. To best present and make the extensive data accessible and user friendly, we have established the Dog10K (http://dog10k.kiz.ac.cn/) database, a comprehensive-omics resource summarizing multiple types of data. This database integrates single nucleotide variants (SNVs) from 1987 canine genomes, de-novo mutations (DNMs) from 43 dog breeds with>40×sequence, RNA-seq data of 105057 single nuclei from hippocampus, 74067 single cells from leukocytesand 30 blood samples from published canid studies. We provide clear visualization, statistics, browse, searching, and downloading functions for all data. We have integrated three analysis tools, Selscan, LiftOver and AgeConversion, to aid researchers in custom exploration of the comprehensive-omics data. The Dog10K database will serve as a foundational platform for analyzing, presenting and utilizing canine multi-omics data.

Variable habitat use supports fine-scale population differentiation of a freshwater piscivore (northern pike, Esox lucius) along salinity gradients in brackish lagoons.

In mobile animals, selection pressures resulting from spatio-temporally varying ecological factors often drive adaptations in migration behavior and associated physiological phenotypes. These adaptations may manifest in ecologically and genetically distinct ecotypes within populations. We studied a meta-population of northern pike (Esox lucius) in brackish environments and examined intrapopulation divergence along environmental gradients. Behavioral phenotypes in habitat use were characterized via otolith microchemistry in 120 individuals sampled from brackish lagoons and adjacent freshwater tributaries. We genotyped 1514 individual pike at 33highly informative genetic markers. The relationship between behavioral phenotype and genotype was examined in a subset of 101 pikes for which both phenotypic and genomic data were available. Thermosaline differences between juvenile and adult life stages indicated ontogenetic shifts from warm, low-saline early habitats towards colder, higher-saline adult habitats. Four behavioral phenotypes were found: Freshwater residents, anadromous, brackish residents, and cross-habitat individuals, the latter showing intermediary habitat use between brackish and freshwater areas. Underlying the behavioral phenotypes were four genotypes,putative freshwater, putativeanadromous, and two putativelybrackish genotypes. Through phenotype-genotype matching, three ecotypes were identified: (i) a brackish resident ecotype, (ii) a freshwater ecotype expressing freshwater residency or anadromy, and (iii) a previously undescribed intermediary cross-habitat ecotype adapted to intermediate salinities, showing limited reliance on freshwater. Life-time growth of all ecotypes was similar, suggesting comparable fitness. Bycombining genetic data with lifelong habitat use and growth as a fitness surrogate, our study revealed strong differentiation in response to abiotic environmental gradients, primarily salinity, indicating ecotype diversity in coastal northern pike is higher than previously believed.

Unravelling the metabolomic signatures of migrant and non-migrant glass eels (Anguilla anguilla) and their response to diazepam exposure

Understanding the migratory cycle of the European eel is crucial for implementing effective conservation measures. The reasons why some glass eels settle in lower estuaries rather than migrating upriver remain unclear. This study aims to identify metabolomic signatures that distinguish active (migrant) from inactive (non-migrant) glass eels. Using a combination of target and non-target screening (NTS) approaches, the metabolite profile of glass eels was studied, and a PLS-DA classification model was applied to find differences between behavioural phenotypes. This model highlighted methionine, glutaryl-L-carnitine, and palmitoylcarnitine as key metabolites, with methionine being significantly different between groups. Glutaryl-L-carnitine strongly correlated with activity, suggesting it might be a more sensitive indicator of glass eel activity than previously studied parameters such as weight loss and oxygen consumption. The findings suggest that differences between active and inactive eels result from both swimming activity and intrinsic metabolic differences, with methionine linked to both factors. We also explored potential differences in how diazepam affects active and inactive glass eels. However, our metabolomic approach lacked the sensitivity to detect significant variations. Overall, this study provides valuable insights into the metabolomic distinctions between active and inactive glass eels, establishing a foundation for future research in this field.

Pheochromocytoma-Paraganglioma Syndrome: A Multiform Disease with Different Genotype and Phenotype Features.

Pheochromocytoma and paraganglioma (PPGL) are rare tumors derived from the adrenal medulla and extra-adrenal chromaffin cells. Diagnosis is often challenging due to the great variability in clinical presentation; the complexity of management due to the dangerous effects of catecholamine excess and the potentially malignant behavior require in-depth knowledge of the pathology and multidisciplinary management. Nowadays, diagnostic ability has certainly improved and guidelines and consensus documents for treatment and follow-up are available. A major impulse to the development of this knowledge has come from the new findings on the genetic and molecular characteristics of PPGLs. Germline mutation in susceptibility genes is detected in 40% of subjects, with a mutation frequency of 10-12% also in patients with sporadic presentation and genetic testing should be incorporated within clinical care. PPGL susceptibility genes include "old genes" associated with Neurofibromatosis type 1 (NF1 gene), Von Hippel Lindau syndrome (VHL gene) and Multiple Endocrine Neoplasia type 2 syndrome (RET gene), the family of SDHx genes (SDHA, SDHB, SDHC, SDHD, SDHAF2), and genes less frequently involved such as TMEM, MAX, and FH. Each gene has a different risk of relapse, malignancy, and other organ involvement; for mutation carriers, affected or asymptomatic, it is possible to define a tailored long-life surveillance program according to the gene involved. In addition, molecular characterization of the tumor has allowed the identification of somatic mutations in other driver genes, bringing to 70% the PPGLs for which we know the mechanisms of tumorigenesis. This has expanded the catalog of tumor driver genes, which are identifiable in up to 70% of patients Integrated genomic and transcriptomic data over the last 10 years have revealed three distinct major molecular signatures, triggered by pathogenic variants in susceptibility genes and characterized by the activation of a specific oncogenic signaling: the pseudo hypoxic, the kinase, and the Wnt signaling pathways. These molecular clusters show a different biochemical phenotype and clinical behavior; they may also represent the prerequisite for implementing customized therapy and follow-up.

Fibroblast growth factor 21: update on genetics and molecular biology.

Since its discovery, most research on fibroblast growth factor 21 (FGF21) has focused on its antihyperglycemia properties. However, attention has recently shifted towards elucidating the ability of FGF21 to lower circulating lipid levels and ameliorate liver inflammation and steatosis. We here discuss the physiology of FGF21 and its role in lipid metabolism, with a focus on genetics, which has up until now not been fully appreciated. New developments have uncovered associations of common small-effect variants of the FGF21 gene, such as the single nucleotide polymorphisms rs2548957 and rs838133, with numerous physiological, biochemical and behavioural phenotypes linked to energy metabolism and liver function. In addition, rare loss-of-function variants of the cellular receptors for FGF21 have been recently associated with severe endocrine and metabolic phenotypes. These associations corroborate the findings from basic studies and preliminary clinical investigations into the therapeutic potential of FGF21 for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD) and hypertriglyceridemia. Furthermore, recent breakthrough research has begun to dissect mechanisms of a potential FGF21 brain-adipose axis. Such inter-organ communication would be comparable to that seen with other potent metabolic hormones. A deeper understanding of FGF21 could prove to be further beneficial for drug development. FGF21 is a potent regulator of lipid and energy homeostasis and its physiology is currently at the centre of investigative efforts to develop agents targeting hypertriglyceridemia and MASLD.

Optimal Instruments for Measurement of Dietary Intake, Physical Activity, and Sleep Among Adults in Population-Based Studies: Report of a National Heart, Lung, and Blood Institute Workshop.

The National Heart, Lung, and Blood Institute convened a virtual workshop in September 2022 to discuss "Optimal Instruments for Measurement of Diet, Physical Activity, and Sleep." This report summarizes the proceedings, identifying current research gaps and future directions for measuring different lifestyle behaviors in adult population-based studies. Key discussions centered on integrating report-based methods, like questionnaires, with device-based assessments, including wearables and physiological measures such as biomarkers and omics to enhance self-reported metrics and better understand the underlying biologic mechanisms of chronic diseases. Emphasis was placed on the need for data harmonization, including the adoption of standard terminology, reproducible metrics, and accessible raw data, to enhance the analysis through artificial intelligence and machine learning techniques. The workshop highlighted the importance of standardizing procedures for integrated behavioral phenotypes using time-series data. These efforts aim to refine data accuracy and comparability across studies and populations, thereby advancing our understanding of lifestyle behaviors and their impact on chronic disease outcomes over the life course.

The Neural Correlations of Olfactory Associative Reward Memories in Drosophila.

Advancing treatment to resolve human cognitive disorders requires a comprehensive understanding of the molecular signaling pathways underlying learning and memory. While most organ systems evolved to maintain homeostasis, the brain developed the capacity to perceive and adapt to environmental stimuli through the continuous modification of interactions within a gene network functioning within a broader neural network. This distinctive characteristic enables significant neural plasticity, but complicates experimental investigations. A thorough examination of the mechanisms underlying behavioral plasticity must integrate multiple levels of biological organization, encompassing genetic pathways within individual neurons, interactions among neural networks providing feedback on gene expression, and observable phenotypic behaviors. Model organisms, such as Drosophila melanogaster, which possess more simple and manipulable nervous systems and genomes than mammals, facilitate such investigations. The evolutionary conservation of behavioral phenotypes and the associated genetics and neural systems indicates that insights gained from flies are pertinent to understanding human cognition. Rather than providing a comprehensive review of the entire field of Drosophila memory research, we focus on olfactory associative reward memories and their related neural circuitry in fly brains, with the objective of elucidating the underlying neural mechanisms, thereby advancing our understanding of brain mechanisms linked to cognitive systems.

Schizophrenia pathology reverse-translated into mouse shows hippocampal hyperactivity, psychosis behaviors and hyper-synchronous events.

Decades of research into the function of the medial temporal lobe has driven curiosity around clinical outcomes associated with hippocampal dysfunction, including psychosis. Post-mortem analyses of brain tissue from human schizophrenia brain show decreased expression of the NMDAR subunit GluN1 confined to the dentate gyrus with evidence of downstream hippocampal hyperactivity in CA3 and CA1. Little is known about the mechanisms of the emergence of hippocampal hyperactivity as a putative psychosis biomarker. We have developed a reverse-translation mouse to study critical neural features. We had previously studied a dentate gyrus (DG)-specific GluN1 KO, which displays hippocampal hyperactivity and a psychosis-relevant behavioral phenotype. Here, we expressed an inhibitory DREADD (pAAV-CaMKIIa-hM4D(Gi)-mCherry) in granule cells of the mouse dentate gyrus, and continuously inhibited the region for 21 days in adolescent (6 weeks) and adult (10 weeks) C57BL/6 J mice with DREADD agonist Compound 21 (C21). Following this period, we quantified activity in the hippocampal subfields by assessing cFos expression, hippocampally mediated behaviors, and hippocampal local field potential with an intracerebral probe with continual monitoring over time. DG inhibition during adolescence generates an increase in hippocampal activity in CA3 and CA1, impairs social cognition and spatial working memory, as well as shows evidence of increased activity in local field potentials as spontaneous synchronous bursts of activity, which we term hyper-synchronous events (HSEs) in hippocampus. The same DG inhibition delivered during adulthood in the mouse lacks these outcomes. These results suggest a sensitive period in development in which the hippocampus is susceptible to DG inhibition resulting in hippocampal hyperactivity and psychosis-like behavioral outcomes.