Sensory Neuron Diversity in the Inner Ear Is Shaped by Activity.

In the auditory system, type I spiral ganglion neurons (SGNs) convey complex acoustic information from inner hair cells (IHCs) to the brainstem. Although SGNs exhibit variation in physiological and anatomical properties, it is unclear which features are endogenous and which reflect input from synaptic partners. Using single-cell RNA sequencing, we derived a molecular classification of mouse type I SGNs comprising three subtypes that express unique combinations of Ca2+ binding proteins, ion channel regulators, guidance molecules, and transcription factors. Based on connectivity and susceptibility to age-related loss, these subtypes correspond to those defined physiologically. Additional intrinsic differences among subtypes and across the tonotopic axis highlight an unexpectedly active role for SGNs in auditory processing. SGN identities emerge postnatally and are disrupted in a mouse model of deafness that lacks IHC-driven activity. These results elucidate the range, nature, and origins of SGN diversity, with implications for treatment of congenital deafness.

Lipid-encapsulated mRNA encoding an extended serum half-life interleukin-22 ameliorates metabolic disease in mice.

OBJECTIVE: Interleukin (IL)-22 is a potential therapeutic protein for the treatment of metabolic diseases such as obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease due to its involvement in multiple cellular pathways and observed hepatoprotective effects. The short serum half-life of IL-22 has previously limited its use in clinical applications; however, the development of mRNA-lipid nanoparticle (LNP) technology offers a novel therapeutic approach that uses a host-generated IL-22 fusion protein. In the present study, the effects of administration of an mRNA-LNP encoding IL-22 on metabolic disease parameters was investigated in various mouse models. METHODS: C57BL/6NCrl mice were used to confirm mouse serum albumin (MSA)-IL-22 protein expression prior to assessments in C57BL/6NTac and CETP/ApoB transgenic mouse models of metabolic disease. Mice were fed either regular chow or a modified amylin liver nonalcoholic steatohepatitis-inducing diet prior to receiving either LNP-encapsulated MSA-IL-22 or MSA mRNA via intravenous or intramuscular injection. Metabolic markers were monitored for the duration of the experiments, and postmortem histology assessment and analysis of metabolic gene expression pathways were performed. RESULTS: MSA-IL-22 was detectable for ≥8 days following administration. Improvements in body weight, lipid metabolism, glucose metabolism, and lipogenic and fibrotic marker gene expression in the liver were observed in the MSA-IL-22-treated mice, and these effects were shown to be durable. CONCLUSIONS: These results support the application of mRNA-encoded IL-22 as a promising treatment strategy for metabolic syndrome and associated comorbidities in human populations.

Runx1 controls auditory sensory neuron diversity in mice.

Sound stimulus is encoded in mice by three molecularly and physiologically diverse subtypes of sensory neurons, called Ia, Ib, and Ic spiral ganglion neurons (SGNs). Here, we show that the transcription factor Runx1 controls SGN subtype composition in the murine cochlea. Runx1 is enriched in Ib/Ic precursors by late embryogenesis. Upon the loss of Runx1 from embryonic SGNs, more SGNs take on Ia rather than Ib or Ic identities. This conversion was more complete for genes linked to neuronal function than to connectivity. Accordingly, synapses in the Ib/Ic location acquired Ia properties. Suprathreshold SGN responses to sound were enhanced in Runx1CKO mice, confirming the expansion of neurons with Ia-like functional properties. Runx1 deletion after birth also redirected Ib/Ic SGNs toward Ia identity, indicating that SGN identities are plastic postnatally. Altogether, these findings show that diverse neuronal identities essential for normal auditory stimulus coding arise hierarchically and remain malleable during postnatal development.

Sex-Specific Role for Dopamine Receptor D2 in Dorsal Raphe Serotonergic Neuron Modulation of Defensive Acoustic Startle and Dominance Behavior.

Brain networks underlying states of social and sensory alertness are normally adaptive, influenced by serotonin and dopamine (DA), and abnormal in neuropsychiatric disorders, often with sex-specific manifestations. Underlying circuits, cells, and molecules are just beginning to be delineated. Implicated is a subtype of serotonergic neuron denoted Drd2-Pet1, distinguished by expression of the type-2 DA receptor (Drd2) gene, inhibited cell-autonomously by DRD2 agonism in slice, and, when constitutively silenced in male mice, affects levels of defensive and exploratory behaviors (Niederkofler et al., 2016). Unknown has been whether DRD2 signaling in these Pet1 neurons contributes to their capacity for shaping defensive behaviors. To address this, we generated mice in which Drd2 gene sequences were deleted selectively in Pet1 neurons. We found that Drd2Pet1-CKO males, but not females, demonstrated increased winning against sex-matched controls in a social dominance assay. Drd2Pet1-CKO females, but not males, exhibited blunting of the acoustic startle response, a protective, defensive reflex. Indistinguishable from controls were auditory brainstem responses (ABRs), locomotion, cognition, and anxiety-like and depression-like behaviors. Analyzing wild-type Drd2-Pet1 neurons, we found sex-specific differences in the proportional distribution of axonal collaterals, in action potential (AP) duration, and in transcript levels of Gad2, important for GABA synthesis. Drd2Pet1-CKO cells displayed sex-specific differences in the percentage of cells harboring Gad2 transcripts. Our results suggest that DRD2 function in Drd2-Pet1 neurons is required for normal defensive/protective behaviors in a sex-specific manner, which may be influenced by the identified sex-specific molecular and cellular features. Related behaviors in humans too show sex differences, suggesting translational relevance.