Highlights 8 • Zebrafish larvae generate swims of increased speed during optomotor 9 response when D1-like receptors are activated. Summary 2 0Animals generate locomotion at different speeds to suit their behavioral needs. 2 1 Spinal circuits generate locomotion at these varying speeds by sequential activation 2 2 of different spinal interneurons and motor neurons. Larval zebrafish can generate 2 3 slow swims for prey capture and exploration by activation of secondary motor 2 4 neurons and much faster and vigorous swims during escapes and struggles via the 2 5 additional activation of primary motor neurons. Neuromodulators are known to alter 2 6 motor output of spinal circuits yet their precise role in speed regulation is not 2 7 understood well. Here, in the context of optomotor response (OMR), an innate, 2 8 evoked locomotor behavior, we show that dopamine (DA) provides an additional 2 9 layer to regulation of swim speed in larval zebrafish. Activation of D1-like receptors 3 0 increases swim speed during OMR in free-swimming larvae. By analysing tail bend 3 1 kinematics in head-restrained larvae, we show that the increase in speed is actuated 3 2 by larger tail bends. Whole cell patch clamp recordings from motor neurons reveal 3 3 that during OMR, typically only secondary motor neurons are active while primary 3 4 motor neurons are quiescent. Activation of D1-like receptors increases motor drive 3 5 from secondary motor neurons by decreasing spike threshold and latency. In 3 6 addition, D1-like receptor activation enhances excitability and recruits quiescent 3 7 primary motor neurons. Our findings provide an example of neuromodulatory 3 8 reconfiguration of spinal motor neuron speed modules such that members are 3 9 selectively recruited and motor drive is increased to effect changes in locomotor 4 0 speed. 4 1 4 2 Keywords 4 3 Dopamine, optomotor response, zebrafish, spinal cord, excitability, D1-like receptor 4 4 3 4 5 Graphical abstract 4 6 4 7 4 8Survival for most animals depends on their ability to adapt speed, gait and 4 9 direction of movement quickly in response to sensory stimuli. In vertebrates, these 5 0 processes are controlled by the concerted activity of distributed circuits in the brain 5 1 and the spinal cord. In particular, the regulation of speed by spinal locomotor circuits 5 2 has received much attention recently. The ability to genetically label specific 5 3 neuronal populations and to target them for imaging or electrophysiology has 5 4 allowed us to identify recruitment patterns of interneurons and motor neurons at 5 5 different speeds. Studies in mice and zebrafish have identified subtypes of spinal 5 6interneurons and motor neurons that are selectively recruited at different speeds of 5 7 locomotion [1-8]. These interneurons and motor neurons make selective synaptic 5 8
Highlights• Zebrafish larvae generate swims of increased speed during optomotor response when D1-like receptors are activated.• D1-like receptor activation increases the extent of tail bending during forward swims and turns resulting in increased swim speed.• Neuromodulation via D1-like receptors increases motor drive by enhancing excitability of 'slow' motor neurons. In addition, D1-like receptor activation recruits quiescent 'fast' motor neurons to increase swim speed.• This demonstrates neuromodulatory selection of motor neurons belonging to different 'speed' modules to alter swimming behavior.
Background: While unopposed estrogen hormone secretion is most commonly implicated in the pathogenesis of endometrial carcinoma, the role of prolactin has only recently been highlighted. The authors present a case of a synchronous endometrial carcinoma in a patient with a prolactin-secreting macroadenoma. Methods: A 29-year-old woman presented with a 4-year history of primary infertility, irregular periods and intermittent galactorrhea. Hormonal evaluation revealed elevated prolactin and subnormal luteinizing hormone and follicle-stimulating hormone (FSH) serum concentrations. An ultrasound of the pelvis revealed endometrial thickening. The MRI of the brain confirmed a pituitary macroadenoma. The patient underwent a resectoscopic polypectomy and dilation and curettage followed by transnasal transsphenoidal excision of the pituitary macroadenoma. Results: The biopsy of the endometrium revealed a well-differentiated endometrioid carcinoma while that of the pituitary tumor confirmed a prolactinoma. Conclusion: An indirect causal mechanism can be postulated to explain this association. Hyperprolactinemia inhibits gonadotropin-releasing hormone leading to subnormal FSH and luteinizing hormone levels. Though the patient is hypoestrogenic, chronic anovulation with unopposed estrogen secretion can increase the risk of endometrial carcinoma. Patients with prolactinomas and irregular menstrual bleeding should undergo endometrial sampling to rule out this possibility.
Autism spectrum disorders (ASDs) are characterized by abnormal behavioral traits arising from neural circuit dysfunction. While a number of genes have been implicated in ASDs, in most cases, a clear understanding of how mutations in these genes lead to circuit dysfunction and behavioral abnormality is absent. The autism susceptibility candidate 2 ( AUTS2 ) gene is one such gene, associated with ASDs, intellectual disability and a range of other neurodevelopmental conditions. However, the role of AUTS2 in neural development and circuit function is not at all known. Here, we undertook functional analysis of Auts2a, the main homolog of AUTS2 in zebrafish, in the context of the escape behavior. Escape behavior in wild-type zebrafish is critical for survival and is therefore, reliable, rapid, and has well-defined kinematic properties. auts2a mutant zebrafish are viable, have normal gross morphology and can generate escape behavior with normal kinematics. However, the behavior is unreliable and delayed, with high trial-to-trial variability in the latency. Using calcium imaging we probed the activity of Mauthner neurons during otic vesicle (OV) stimulation and observed lower probability of activation and reduced calcium transients in the mutants. With direct activation of Mauthner by antidromic stimulation, the threshold for activation in mutants was higher than that in wild-type, even when inhibition was blocked. Taken together, these results point to reduced excitability of Mauthner neurons in auts2a mutant larvae leading to unreliable escape responses. Our results show a novel role for Auts2a in regulating neural excitability and reliability of behavior.
Autism spectrum disorders (ASDs) are characterized by abnormal behavioral traits arising from neural circuit dysfunction. While a number of genes have been implicated in ASDs, in most cases, a clear understanding of how mutations in these genes lead to circuit dysfunction and behavioral abnormality is absent. The autism susceptibility candidate 2 (AUTS2) gene is one such gene, associated with ASDs, intellectual disability and a range of other neurodevelopmental conditions. Yet, the function of AUTS2 in neural development and circuit function is not at all known. Here, we undertook functional analysis of Auts2a, the main homolog of AUTS2 in zebrafish, in the context of the escape behavior. Escape behavior in wild type zebrafish is critical for survival and is therefore, reliable, rapid, and has well-defined kinematic properties. Auts2a-/- zebrafish are viable, have normal gross morphology and can generate escape behavior with normal kinematics. However, the behavior is unreliable and delayed, with high trial-to-trial variability in the latency. We demonstrate that this is due to the reduced excitability of Mauthner neurons resulting in unreliable firing with stimuli that normally elicit the escape response. Combined with previous studies that show Auts2-regulation of the transcription of ion channel proteins, our results suggest that Auts2 sets the excitability of neurons by activating a set transcriptional program.
A 26-year-old phenotypic sexually active female presented with primary amenorrhea and 5 years infertility. Patient's height was 171 cm and weight 70 kg. Physical examination showed normal development of breast (Tanner stage 2) with no pubic and axillary hairs and blind vaginal pouch of 2 cm.MRI revealed a hypoplastic uterus with an absent cervix and upper vagina and two oblong enhancing soft tissue structures with small cysts in both inguinal canals adjacent
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