Highlights d SOX2 is expressed in SCN clock neurons and activates Period2 gene transcription d Ablation of SOX2 in SCN neurons severely disrupts circadian behavioral rhythms d SOX2 promotes the robust expression of neuropeptides and their receptors in the SCN d Ablation of SOX2 alters the transcriptional landscape of the SCN

This large, single-center series demonstrates that H-type TEF can be diagnosed with esophagogram at an early age. Postoperative recurrent laryngeal nerve paresis and gastro-esophageal reflux disease are common following repair. Although most patients with vocal cord paresis eventually become asymptomatic, two-thirds do not regain vocal cord function. This reinforces the importance of routine examination of vocal cord movement following H-type TEF repair.

The principal circadian pacemaker in mammals, the suprachiasmatic nucleus (SCN), expresses a number of neuropeptides that facilitate intercellular synchrony, helping to generate coherent outputs to peripheral clocks throughout the body. In particular, arginine vasopressin (AVP)– and vasoactive intestinal peptide (VIP)–expressing neurons have been recognized as crucial subpopulations within the SCN and have thus been the focus of many chronobiological studies. Here, we analyze the neuropeptide expression of 2 popular transgenic mouse strains commonly used to direct or restrict Cre-mediated recombination to AVP- and VIP-ergic neurons. The Avp-IRES2-Cre (JAX #023530) and Vip-IRES-Cre (JAX #010908) “driver” mouse strains express the Cre recombinase under the control of the endogenous Avp or Vip gene, respectively, allowing scientists either to ablate their gene of interest or to overexpress a transgene in a cell type–specific manner. Although these are potentially very powerful tools for chronobiologists and other scientists studying AVP- and VIP-ergic neurons, we found that neuropeptide expression in these mice is significantly decreased when an IRES(2)-Cre cassette is inserted downstream of the neuropeptide-encoding gene locus. The impact of IRES(2)-Cre cassette insertion on neuropeptide expression may be a confounding factor in many experimental designs. Our findings suggest that extreme caution must be exercised when using these mouse models to avoid misinterpretation of empirical results.

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Somatosensation encompasses a variety of essential modalities including touch, pressure, proprioception, temperature, pain, and itch. These peripheral sensations are crucial for all types of behaviors, ranging from social interaction to danger avoidance. Somatosensory information is transmitted from primary afferent fibers in the periphery into the central nervous system via the dorsal horn of the spinal cord. The dorsal horn functions as an intermediary processing center for this information, comprising a complex network of excitatory and inhibitory interneurons as well as projection neurons that transmit the processed somatosensory information from the spinal cord to the brain. It is now known that there can be dysfunction within this spinal cord circuitry in pathological pain conditions and that these perturbations contribute to the development and maintenance of pathological pain. However, the complex and heterogeneous network of the spinal dorsal horn has hampered efforts to further elucidate its role in somatosensory processing. Emerging optical techniques promise to illuminate the underlying organization and function of the dorsal horn and provide insights into the role of spinal cord sensory processing in shaping the behavioral response to somatosensory input that we ultimately observe. This review article will focus on recent advances in optogenetics and fluorescence imaging techniques in the spinal cord, encompassing findings from both in vivo and in vitro preparations. We will also discuss the current limitations and difficulties of employing these techniques to interrogate the spinal cord and current practices and approaches to overcome these challenges.

Mood disorders negatively impact the lives of hundreds of millions of individuals worldwide every year, yet the precise molecular mechanisms by which they manifest remain elusive. Circadian dysregulation is one avenue by which mood disorders are thought to arise. SOX2 is a transcription factor that is highly expressed in the murine suprachiasmatic nucleus (SCN), the circadian master clock, and has been recently found to be an important regulator of Per2, a core component of the molecular clock. Genetic ablation of the Sox2 gene in GABAergic neurons selectively impacts SCN neurons, as they are one of very few, if not the only, GABAergic populations that express Sox2. Here, we show that GABAergic-restricted ablation of Sox2 results in anxio-depressive-like phenotypes in mice as observed in the elevated plus maze, forced swim test, tail suspension test, and sucrose preference test. We further observe a reduction in basal and/or forced swim-induced c-Fos expression, a marker of neuronal activation, in the nucleus incertus, arcuate nucleus, and dentate gyrus of Sox2 conditional knockout (cKO) mice. Given the restricted disruption of SOX2 expression in the SCN of Sox2 cKO mice, we propose that their mood-associated phenotypes are the consequence of a dysregulated central clock that is unable to communicate appropriately timed signals to other brain nuclei that regulate affective behaviors.

Chronic, pathological pain is a highly debilitating condition that can arise and be maintained through central sensitization. Central sensitization shares mechanistic and phenotypic parallels with memory formation. In a sensory model of memory reconsolidation, plastic changes underlying pain hypersensitivity can be dynamically regulated and reversed following the reactivation of sensitized sensory pathways. However, the mechanisms by which synaptic reactivation induces destabilization of the spinal “pain engram” are unclear. We identified nonionotropic N -methyl- d -aspartate receptor (NI-NMDAR) signaling as necessary and sufficient for the reactive destabilization of dorsal horn long-term potentiation and the reversal of mechanical sensitization associated with central sensitization. NI-NMDAR signaling engaged directly or through the reactivation of sensitized sensory networks was associated with the degradation of excitatory postsynaptic proteins. Our findings identify NI-NMDAR signaling as a putative synaptic mechanism by which engrams are destabilized in reconsolidation and as a potential means of treating underlying causes of chronic pain.

In mammals, the hypothalamic suprachiasmatic nucleus (SCN) functions as the central circadian pacemaker, orchestrating behavioral and physiological rhythms in alignment to the environmental light/dark cycle. The neurons that comprise the SCN are anatomically and functionally heterogeneous, but despite their physiological importance, little is known about the pathways that guide their specification and differentiation. Here, we report that the stem/progenitor cell transcription factor, Sex determining region Y-box 2 (Sox2), is required in the embryonic SCN to control the expression of SCN-enriched neuropeptides and transcription factors. Ablation of Sox2 in the developing SCN leads to downregulation of circadian neuropeptides as early as embryonic day (E) 15.5, followed by a decrease in the expression of two transcription factors involved in SCN development, Lhx1 and Six6, in neonates. Thymidine analog-retention assays revealed that Sox2 deficiency contributed to reduced survival of SCN neurons during the postnatal period of cell clearance, but did not affect progenitor cell proliferation or SCN specification. Our results identify SOX2 as an essential transcription factor for the proper differentiation and survival of neurons within the developing SCN.