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It has long been known that orofacial movements for feeding can be triggered, coordinated, and often rhythmically organized at the level of the brainstem, without input from higher centers. We uncover two nuclei that can organize the movements for ingesting fluids in mice. These neuronal groups, IRtPhox2b and Peri5Atoh1, are marked by expression of the panautonomic homeobox gene Phox2b and are located, respectively, in the intermediate reticular formation of the medulla and around the motor nucleus of the trigeminal nerve. They are premotor to all jaw-opening and tongue muscles. Stimulation of either, in awake animals, opens the jaw, while IRtPhox2b alone also protracts the tongue. Moreover, stationary stimulation of IRtPhox2b entrains a rhythmic alternation of tongue protraction and retraction, synchronized with jaw opening and closing, that mimics lapping. Finally, fiber photometric recordings show that IRtPhox2b is active during volitional lapping. Our study identifies one of the subcortical nuclei underpinning a stereotyped feeding behavior. [ABSTRACT FROM AUTHOR]

The article talks about the CO2 and H+ concentrations in the arterial blood. The key element of this circuitry is the retrotrapezoid nucleus (RTN) that is activated by increased CO2 or low pH and project to the respiratory rhythm generator. Here, intersectional genetic strategies to lesion the RTN neurons defined by Atoh1 and Phox2b expression. Glutamatergic transmission in cells curtails the phrenic nerve response to low pH.

Key points The respiratory oscillator of the pre-Bötzinger complex (preBötC) can generate distinct inspiratory motor patterns underlying eupnoeic and sigh-related rhythmic activities., The preBötC can generate 'fictive' eupnoea at embryonic stages, but its ability to also generate sigh-like activity remains unexplored at prenatal stages., Here, using mouse brainstem slice preparations, we show that sigh-like activity emerges during embryonic development but later than eupnoeic rhythmogenesis. Inspiratory cells active during the latter are also active during fictive sighing, although a small subset of neurons was found to fire exclusively during sighs. Effective glycinergic inhibitory signalling is also required for sigh generation., We conclude that the developmental emergence of a sigh-generating capability occurs after the onset of eupnoeic rhythmogenesis and requires an appropriate maturational state of chloride-mediated glycinergic synaptic transmission., Abstract In mammals, eupnoeic breathing is periodically interrupted by spontaneous augmented breaths (sighs) that include a larger-amplitude inspiratory effort, typically followed by a post-sigh apnoea. Previous in vitro studies in newborn rodents have demonstrated that the respiratory oscillator of the pre-Bötzinger complex (preBötC) can generate the distinct inspiratory motor patterns for both eupnoea- and sigh-related behaviour. During mouse embryonic development, the preBötC begins to generate eupnoeic rhythmicity at embryonic day (E) 15.5, but the network's ability to also generate sigh-like activity remains unexplored at prenatal stages. Using transverse brainstem slice preparations we monitored the neuronal population activity of the preBötC at different embryonic ages. Spontaneous sigh-like rhythmicity was found to emerge progressively, being expressed in 0/32 slices at E15.5, 7/30 at E16.5, 9/22 at E17.5 and 23/26 at E18.5. Calcium imaging showed that the preBötC cell population that participates in eupnoeic-like discharge was also active during fictive sighs. However, patch-clamp recordings revealed the existence of an additional small subset of neurons that fired exclusively during sigh activity. Changes in glycinergic inhibitory synaptic signalling, either by pharmacological blockade, functional perturbation or natural maturation of the chloride co-transporters KCC2 or NKCC1 selectively, and in an age-dependent manner, altered the bi-phasic nature of sigh bursts and their coordination with eupnoeic bursting, leading to the generation of an atypical monophasic sigh-related event. Together our results demonstrate that the developmental emergence of a sigh-generating capability occurs after the onset of eupnoeic rhythmogenesis and requires the proper maturation of chloride-mediated glycinergic synaptic transmission. [ABSTRACT FROM AUTHOR]

Background: Expansion of multi-C2H2 domain zinc finger (ZNF) genes, including the Krüppel-associated box (KRAB) subfamily, paralleled the evolution of tetrapodes, particularly in mammalian lineages. Advances in their cataloging and characterization suggest that the functions of the KRAB-ZNF gene family contributed to mammalian speciation. Results: Here, we characterized the human 8q24.3 ZNF cluster on the genomic, the phylogenetic, the structural and the transcriptome level. Six (ZNF7, ZNF34, ZNF250, ZNF251, ZNF252, ZNF517) of the seven locus members contain exons encoding KRAB domains, one (ZNF16) does not. They form a paralog group in which the encoded KRAB and ZNF protein domains generally share more similarities with each other than with other members of the human ZNF superfamily. The closest relatives with respect to their DNA-binding domain were ZNF7 and ZNF251. The analysis of orthologs in therian mammalian species revealed strong conservation and purifying selection of the KRAB-A and zinc finger domains. These findings underscore structural/functional constraints during evolution. Gene losses in the murine lineage (ZNF16, ZNF34, ZNF252, ZNF517) and potential protein truncations in primates (ZNF252) illustrate ongoing speciation processes. Tissue expression profiling by quantitative real-time PCR showed similar but distinct patterns for all tested ZNF genes with the most prominent expression in fetal brain. Based on accompanying expression signatures in twenty-six other human tissues ZNF34 and ZNF250 revealed the closest expression profiles. Together, the 8q24.3 ZNF genes can be assigned to a cerebellum, a testis or a prostate/thyroid subgroup. These results are consistent with potential functions of the ZNF genes in morphogenesis and differentiation. Promoter regions of the seven 8q24.3 ZNF genes display common characteristics like missing TATA-box, CpG island-association and transcription factor binding site (TFBS) modules. Common TFBS modules partly explain the observed expression pattern similarities. Conclusions: The ZNF genes at human 8q24.3 form a relatively old mammalian paralog group conserved in eutherian mammals for at least 130 million years. The members persisted after initial duplications by undergoing subfunctionalizations in their expression patterns and target site recognition. KRAB-ZNF mediated repression of transcription might have shaped organogenesis in mammalian ontogeny. [ABSTRACT FROM AUTHOR]

Brain-derived neurotrophic factor (BDNF) is required during the prenatal period for normal development of the respiratory central command; however, the underlying mechanisms remain unknown. To approach this issue, the present study examined BDNF regulation of fetal respiratory rhythm generation in the preBötzinger complex (preBötC) of the mouse, using transverse brainstem slices obtained from prenatal day 16.5 animals. BDNF application (100 ng/mL, 15 min) increased the frequency of rhythmic population activity in the preBötC by 43%. This effect was not observed when preparations were exposed to nerve growth factor (100 ng/mL, 30 min) or pretreated with the tyrosine kinase inhibitor K252a (1 h, 200 nm), suggesting that BDNF regulation of preBötC activity requires activation of its cognate tyrosine receptor kinase, TrkB. Consistent with this finding, single-cell reverse transcription-polymerase chain reaction experiments showed that one third of the rhythmically active preBötC neurons analysed expressed TrkB mRNA. Moreover, 20% expressed BDNF mRNA, suggesting that the preBötC is both a target and a source of BDNF. At the network level, BDNF augmented activity of preBötC glutamatergic neurons and potentiated glutamatergic synaptic drives in respiratory neurons by 34%. At the cellular level, BDNF increased the activity frequency of endogenously bursting neurons by 53.3% but had no effect on basal membrane properties of respiratory follower neurons, including the Ih current. Our data indicate that BDNF signalling through TrkB can acutely modulate fetal respiratory rhythm in association with increased glutamatergic drive and bursting activity in the preBötC. [ABSTRACT FROM AUTHOR]