Recruitment of Motoneurons.

Beginning about half a century ago, the rules that determine how motor units are recruited during movement have been deduced. These classical experiments led to the formulation of the 'size principle'. It is now clear that motoneuronal size is not the only indicator of recruitment order. In fact, motoneuronal passive, active and synaptic conductances are carefully tuned to achieve sequential recruitment. More recent studies, over the last decade or so, show that the premotor circuitry is also functionally specialized and differentially recruited. Modular sub networks of interneurons and their post-synaptic motoneurons have been shown to drive movements with varying intensities. In addition, these modular networks are under the influence of neuromodulators, which are capable of acting upon multiple motor and premotor targets, thereby altering behavioral outcomes. We discuss the recruitment patterns of motoneurons in light of these new and exciting studies.

High Behavioral Variability Mediated by Altered Neuronal Excitability in auts2 Mutant Zebrafish.

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.

Neuromodulatory Selection of Motor Neuron Recruitment Patterns in a Visuomotor Behavior Increases Speed.

Animals generate locomotion at different speeds to suit their behavioral needs. Spinal circuits generate locomotion at these varying speeds by sequential activation of different spinal interneurons and motor neurons. Larval zebrafish can generate slow swims for prey capture and exploration by activation of secondary motor neurons and much faster and vigorous swims during escape and struggle via additional activation of primary motor neurons. Neuromodulators are known to alter the motor output of spinal circuits, but their precise role in speed regulation is not well understood. Here, in the context of optomotor response (OMR), an innate evoked locomotor behavior, we show that dopamine (DA) provides an additional layer to regulation of swim speed in larval zebrafish. Activation of D1-like receptors increases swim speed during OMR in free-swimming larvae. By analyzing tail bend kinematics in head-restrained larvae, we show that the increase in speed is actuated by larger tail bends. Whole-cell patch-clamp recordings from motor neurons reveal that, during OMR, typically only secondary motor neurons are active, whereas primary motor neurons are quiescent. Activation of D1-like receptors increases intrinsic excitability and excitatory synaptic drive in primary and secondary motor neurons. These actions result in greater recruitment of motor neurons during OMR. Our findings provide an example of neuromodulatory reconfiguration of spinal motor neuron speed modules where members are selectively recruited and motor drive is increased to effect changes in locomotor speed. VIDEO ABSTRACT.

Synchronous endometrial carcinoma and a macroprolactinoma: exploring a causal relationship.

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.