SUMMARY Itch is the least well understood of all the somatic senses, and the neural circuits that underlie this sensation are poorly defined. Here we show that the atonal-related transcription factor Bhlhb5 is transiently expressed in the dorsal horn of the developing spinal cord and appears to play a role in the formation and regulation of pruritic (itch) circuits. Mice lacking Bhlhb5 develop self-inflicted skin lesions and show significantly enhanced scratching responses to pruritic agents. Through genetic fate-mapping and conditional ablation we provide evidence that the pruritic phenotype in Bhlhb5 mutants may be due to selective loss of a subset of inhibitory interneurons in the dorsal horn. Our findings suggest that Bhlhb5 is required for the survival of a specific population of inhibitory interneurons that regulate pruritis and provide evidence that the loss of inhibitory synaptic input results in abnormal itch.

Most neurons in vertebrates make a developmental choice between two principal neurotransmitter phenotypes (glutamatergic versus GABAergic). Here we show that the homeobox gene Lbx1 determines a GABAergic cell fate in the dorsal spinal cord at early embryonic stages. In Lbx1-/- mice, the presumptive GABAergic neurons are transformed into glutamatergic cells. Furthermore, overexpression of Lbx1 in the chick spinal cord is sufficient to induce GABAergic differentiation. Paradoxically, Lbx1 is also expressed in glutamatergic neurons. We previously reported that the homeobox genes Tlx1 and Tlx3 determine glutamatergic cell fate. Here we show that impaired glutamatergic differentiation, observed in Tlx3-/- mice, is restored in Tlx3-/-Lbx1-/- mice. These genetic studies suggest that Lbx1 expression defines a basal GABAergic differentiation state, and Tlx3 acts to antagonize Lbx1 to promote glutamatergic differentiation.

The dorsal spinal cord synthesizes a variety of neuropeptides that modulate the transmission of nociceptive sensory information. Here, we used genetic fate mapping to show that Tlx3 ϩ spinal cord neurons and their derivatives represent a heterogeneous population of neurons, marked by partially overlapping expression of a set of neuropeptide genes, including those encoding the anti-opioid peptide cholecystokinin, pronociceptive Substance P (SP), Neurokinin B, and a late wave of somatostatin. Mutations of Tlx3 and Tlx1 result in a loss of expression of these peptide genes. Brn3a, a homeobox transcription factor, the expression of which is partly dependent on Tlx3, is required specifically for the early wave of SP expression. These studies suggest that Tlx1 and Tlx3 operate high in the regulatory hierarchy that coordinates specification of dorsal horn pain-modulatory peptidergic neurons.

Spatial and temporal cues govern the genesis of a diverse array of neurons located in the dorsal spinal cord, including dI1-dI6, dIL A , and dIL B subtypes, but their physiological functions are poorly understood. Here we generated a new line of conditional knock-out (CKO) mice, in which the homeobox gene Tlx3 was removed in dI5 and dIL B cells. In these CKO mice, development of a subset of excitatory neurons located in laminae I and II was impaired, including itch-related GRPR-expressing neurons, PKC␥-expressing neurons, and neurons expressing three neuropeptide genes: somatostatin, preprotachykinin 1, and the gastrin-releasing peptide. These CKO mice displayed marked deficits in generating nocifensive motor behaviors evoked by a range of pain-related or itch-related stimuli. The mutants also failed to exhibit escape response evoked by dynamic mechanical stimuli but retained the ability to sense innocuous cooling and/or warm. Thus, our studies provide new insight into the ontogeny of spinal neurons processing distinct sensory modalities.

Neurons in the mouse dorsal root ganglia (DRG) are composed of a variety of sensory modalities, such as pain-related nociceptors, itch-related pruriceptors, and thermoceptors. All these neurons are derived from late-born neurons that are initially marked by the expression of the nerve growth factor receptor TrkA. During perinatal and postnatal development, these TrkA lineage neurons are globally segregated into Ret-expressing and TrkA-expressing subtypes, and start to express a variety of sensory receptors and ion channels. The runt domain transcription factor Runx1 plays a pivotal role in controlling these developmental processes, but it remains unclear how it works. Here we showed that the homeodomain transcription factor Tlx3, expressed broadly in DRG neurons, is required to establish most Runx1-dependent phenotypes, including the segregation of TrkA-expressing versus Ret-expressing neurons and the expression of a dozen of sensory channels and receptors implicated in sensing pain, itch and temperature. Expression of Runx1 and Tlx3 is independent of each other at prenatal stages when they first establish the expression of these channels and receptors. Moreover, overexpression of Runx1 plus Tlx3 was able to induce ectopic expression of sensory channels and receptors. Collectively, these studies suggest that genetically Tlx3 acts in combination with Runx1 to control the development of a cohort of nocicepotors, thermoceptors and pruriceptors in mice.

The combination of GEPT extracts can reduce levels of endogenous Abeta peptide in APPV717I transgenic mice through the inhibition of PS1 activity rather than BACE1 and the promotion of IDE and NEP activity. Lower-expression of PS1 and over-expression of IDE or NEP may be helpful in potentially lowering brain Abeta levels in subjects with AD, and hence GEPT appears to offer potential that should be explored in AD.

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Digestive diseases are one of the common broiler diseases that significantly affect production and animal welfare in broiler breeding. Droppings examination and observation are the most precise techniques to detect the occurrence of digestive disease infections in birds. This study proposes an automated broiler digestive disease detector based on a deep Convolutional Neural Network model to classify fine-grained abnormal broiler droppings images as normal and abnormal (shape, color, water content, and shape&water). Droppings images were collected from 10,000 25-35-day-old Ross broiler birds reared in multilayer cages with automatic droppings conveyor belts. For comparative purposes, Faster R-CNN and YOLO-V3 deep Convolutional Neural Networks were developed. The performance of YOLO-V3 was improved by optimizing the anchor box. Faster R-CNN achieved 99.1% recall and 93.3% mean average precision, while YOLO-V3 achieved 88.7% recall and 84.3% mean average precision on the testing data set. The proposed detector can provide technical support for the detection of digestive diseases in broiler production by automatically and nonintrusively recognizing and classifying chicken droppings.