Biology subjects

Blechman, J.

Publications and source records attributed to Blechman, J..

6 recordsLinked to original sources

bioRxiv2025

Disruption of the developmental factor Otp in the adult forebrain reveals its diverse physiological functions

Orthopedia (Otp) transcription factor is a critical determinant in the development of the neuroendocrine hypothalamus, and its embryonic deletion results in lethality. Although Otp expression is maintained throughout life, its physiological function in adulthood is not well understood. Here, we generated a forebrain-specific, tamoxifen-inducible, conditional knockout mouse model to investigate the roles of Otp beyond development. Conditional deletion of Otp in two-month-old mice resulted in impaired stress responses, characterized by increased depressive-like behavior and elevated stress-induced cortisol levels. It also led to various metabolic changes, including reduced thyroid hormone levels and body temperature, a higher percentage of fat mass, and diminished responsiveness to ghrelin without affecting food intake, energy expenditure, or body weight. This composite metabolic phenotype was associated with reduced hypothalamic neuropeptides TRH, CRH, AgRP, and NPY expression. Our findings highlight the role of Otp in adult physiological functions as a key neuroendocrine integrator of adaptive stress response and energy balance.

neuroscience↗

bioRxiv2020

Developmental effects of oxytocin neurons on social affiliation and processing of social information

Hormones regulate behavior either through activational effects that facilitate the acute expression of specific behaviors or through organizational effects that shape the development of the nervous system thereby altering adult behavior. Much research has implicated the neuropeptide oxytocin (OXT) in acute modulation of various aspects of social behaviors across vertebrate species, and OXT signaling is associated with the developmental social deficits observed in autism spectrum disorders, however, little is known about the role of OXT in the neurodevelopment of the social brain. We show that perturbation of OXT neurons during early zebrafish development led to a loss of dopaminergic neurons, associated with visual processing and reward, and blunted the neuronal response to social stimuli in the adult brain. Ultimately, adult fish whose OXT neurons were ablated in early life, displayed altered functional connectivity within social decision-making brain nuclei both in naive state and in response to social stimulus and became less social. We propose that OXT neurons have an organizational role, namely to shape forebrain neuroarchitecture during development and to acquire an affiliative response towards conspecifics. Significance StatementSocial behavior is developed over the lifetime of an organism and the neuropeptide oxytocin modulates social behaviors across vertebrate species, and is associated with neuro-developmental social deficits such as autism. However, whether oxytocin plays a role in the developmental maturation of neural systems that are necessary for social behavior remains poorly explored. We show that proper behavioral and neural response to social stimuli depends on a developmental process orchestrated by oxytocin neurons. Animals whose oxytocin system is ablated in early life show blunted neuronal and behavioral responses to social stimuli as well as wide ranging disruptions in the functional connectivity of the Social Brain. We provide a window into the mechanisms underlying oxytocin-dependent developmental processes that implement adult sociality.

neuroscience↗

bioRxiv2020

Genetic variation in the social environment affects behavioral phenotypes of oxytocin receptor mutants in zebrafish

Oxytocin-like peptides have been implicated in the regulation of a wide range of social behaviors across taxa. On the other hand, the social environment, which is composed of conspecifics genotypes, is also known to influence the development of social behavior, creating the possibility for indirect genetic effects. Here we used a knockout line for the oxytocin receptor in zebrafish to investigate how the genotypic composition of the social environment (Es) interacts with the oxytocin genotype (G) of the focal individual in the regulation of its social behavior. For this purpose, we have raised wild-type or knock-out zebrafish in either wild-type or knock-out shoals and tested different components of social behavior in adults. GxEs effects were detected in some behaviors, highlighting the need to control for GxEs effects when interpreting results of experiments using genetically modified animals, since the social environment can either rescue or promote phenotypes associated with specific genes.

ecology↗

bioRxiv2019

Single-cell molecular and cellular architecture of neurohypophyseal cell types in the adult mouse

The neurohypophysis (NH), located at the posterior lobe of the pituitary, is a major neuroendocrine tissue, which mediates osmotic balance, blood pressure, reproduction, and lactation by means of releasing the neurohormones oxytocin and arginine-vasopressin from the brain into the peripheral blood circulation. The major cellular components of the NH are hypothalamic axonal termini, fenestrated endothelia and pituicytes, the resident astroglia. However, despite the physiological importance of the NH, the exact molecular signature defining neurohypophyseal cell types and in particular the pituicytes, remains unclear. Using single cell RNA sequencing, we captured seven distinct cell types in the NH and intermediate lobe (IL) of adult male mouse. We revealed novel pituicyte markers showing higher specificity than previously reported. Single molecule in situ hybridization revealed spatial organization of the major cell types implying intercellular communications. We present a comprehensive molecular and cellular characterization of neurohypophyseal cell-types serving as a valuable resource for further functional research.\n\nSignificance StatementThe neurohypophysis (NH) is a major neuroendocrine interface, which allows the brain to regulate the function of peripheral organs in response to specific physiological demands. Despite its importance, a comprehensive molecular description of cell identities in the NH is still lacking. Utilizing single cell RNA sequencing technology, we identified the transcriptomes of five major neurohypophyseal cell types in the adult male mice and mapped the spatial distribution of selected cell types in situ. We revealed an unexpected cellular heterogeneity of the neurohypophysis and provide novel molecular markers for neurohypophyseal cell types with higher specificity than previously reported.

neuroscience↗

bioRxiv2019

Fenestrae-associated protein Plvap regulates the rate of blood-borne proteins passage into the hypophysis

To maintain body homeostasis, endocrine systems must detect and integrate a multitude of blood-borne peripheral signals. This is mediated by specialized permeable pores in the endothelial membrane, dubbed fenestrae. Plasmalemma vesicles-associated protein (Plvap) is located in the fenestral diaphragm and is thought play a role in the selective passage of proteins through the fenestrae. However, this suggested function has yet to be demonstrated directly. Here, we studied the development of fenestrated capillaries in a major neuroendocrine interface between the blood and brain, namely the hypophysis. Using a transgenic permeability biosensor to visualize the vascular excretion of a genetically tagged plasma protein (DBP-EGFP), we show that the developmental acquisition of vascular permeability is associated with differential expression of zebrafish plvap orthologs in the hypophysis versus brain. Ultrastructural analysis of the hypophyseal vasculature revealed that plvapb mutants display deficiencies in fenestral and stomatal diaphragms as well as increased density of fenestrae, but not of caveolae. Measurements of DBP-EGFP dynamics in live plvapb mutant larvae provided a direct proof that Plvap limits the rate of blood-borne protein passage through fenestrated endothelia. Overall, we present the regulatory role of Plvap in the development of blood-borne protein detection machinery in a major neuroendocrine interface between the brain and the general circulation.

developmental biology↗

bioRxiv2019

Robo2 regulates synaptic oxytocin content by affecting actin state

The regulation of neuropeptide level at the site of release is essential for proper neurophysiological functions. We focused on a prominent neuropeptide, oxytocin (OXT), and used the zebrafish as an in vivo model to visualize and quantify OXT content at the resolution of a single synapse. We found that OXT-loaded synapses were surrounded by polymerized actin. Perturbation of actin filaments by cytochalasin-D resulted in decreased synaptic OXT levels. Live imaging of the actin probe, Lifeact-EGFP, showed reduced mobility in OXT synapses in robo2 mutants, which displayed decreased synaptic OXT content. Using a novel transgenic reporter line allowing real-time monitoring of OXT-loaded vesicles, we showed that robo2 mutants display slower rate of vesicles accumulation. OXT-specific expression of dominant-negative Cdc42, which is a key regulator of actin dynamics and a downstream effector of Robo2, led to a dose-dependent increase in OXT content in WT, and a dampened effect in robo2 mutants. Our results link Robo2-Cdc42 signalling, which controls local actin dynamics, with the maintenance of synaptic neuropeptide levels.

developmental biology↗