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Metabolic dysfunction-associated steatohepatitis (MASH) is the progressive form of liver steatosis, the most common liver disease, and substantially increases the mortality rate. However, limited therapies are currently available to prevent MASH development. Identifying potential pharmacological treatments for the condition has been hampered by its heterogeneous and complex nature. Here, we identified a hepatic nonneuronal cholinergic signaling pathway required for metabolic adaptation to caloric overload. We found that cholinergic receptor nicotinic alpha 2 subunit (CHRNA2) is highly expressed in hepatocytes of mice and humans. Further, CHRNA2 is activated by a subpopulation of local acetylcholine-producing macrophages during MASH development. The activation of CHRNA2 coordinates defensive programs against a broad spectrum of MASH-related pathogenesis, including steatosis, inflammation, and fibrosis. Hepatocyte-specific loss of CHRNA2 signaling accelerates the disease onset in different MASH mouse models. Activation of this pathway via pharmacological inhibition of acetylcholine degradation protects against MASH development. Our study uncovers a hepatic nicotinic cholinergic receptor pathway that constitutes a cell-autonomous self-defense route against prolonged metabolic stress and holds therapeutic potential for combatting human MASH. The complexity of metabolic dysfunction-associated steatohepatitis (MASH) has impaired the development of pharmacological treatments for the condition. This study shows that nicotinic acetylcholine receptor signaling serves as an intrinsic protective mechanism against extended metabolic stress in the liver. [ABSTRACT FROM AUTHOR]

Hippocampal somatostatin-expressing (Sst) GABAergic interneurons (INs) exhibit considerable anatomical and functional heterogeneity. Recent single-cell transcriptome analyses have provided a comprehensive Sst-IN subpopulations census, a plausible molecular ground truth of neuronal identity whose links to specific functionality remain incomplete. Here, we designed an approach to identify and access subpopulations of Sst-INs based on transcriptomic features. Four mouse models based on single or combinatorial Cre-and Flp-expression differentiated functionally distinct subpopulations of CA1 hippocampal Sst-INs that largely tiled the morpho-functional parameter space of the Sst-INs superfamily. Notably, the Sst;;Tac1 intersection revealed a population of bistratified INs that preferentially synapsed onto fast-spiking interneurons (FS-INs) and were sufficient to interrupt their firing. In contrast, the Ndnf;;Nkx2-1 intersection identified a population of oriens lacunosum-moleculare INs that predominantly targeted CA1 pyramidal neurons, avoiding FS-INs. Overall, our results provide a framework to translate neuronal transcriptomic identity into discrete functional subtypes that capture the diverse specializations of hippocampal Sst-INs. [ABSTRACT FROM AUTHOR]

Locomotion in mammals relies on a central pattern-generating circuitry of spinal interneurons established during development that coordinates limb movement. These networks produce left-right alternation of limbs as well as coordinated activation of flexor and extensor muscles. Here we show that a premature stop codon in the DMRT3 gene has a major effect on the pattern of locomotion in horses. The mutation is permissive for the ability to perform alternate gaits and has a favourable effect on harness racing performance. Examination of wild-type and Dmrt3-null mice demonstrates that Dmrt3 is expressed in the dI6 subdivision of spinal cord neurons, takes part in neuronal specification within this subdivision, and is critical for the normal development of a coordinated locomotor network controlling limb movements. Our discovery positions Dmrt3 in a pivotal role for configuring the spinal circuits controlling stride in vertebrates. The DMRT3 mutation has had a major effect on the diversification of the domestic horse, as the altered gait characteristics of a number of breeds apparently require this mutation.

In the spinal cord, sensory‐motor circuits controlling motor activity are situated in the dorso–ventral interface. The neurons identified by the expression of the transcription factor Doublesex and mab‐3 related transcription factor 3 (Dmrt3) have previously been associated with the coordination of locomotion in horses (Equus caballus, Linnaeus, 1758), mice (Mus musculus, Linnaeus, 1758), and zebrafish (Danio rerio, F. Hamilton, 1822). Based on earlier studies, we hypothesized that, in mice, these neurons may be positioned to receive sensory and central inputs to relay processed commands to motor neurons. Thus, we investigated the presynaptic inputs to spinal Dmrt3 neurons using monosynaptic retrograde replication‐deficient rabies tracing. The analysis showed that lumbar Dmrt3 neurons receive inputs from intrasegmental neurons, and intersegmental neurons from the cervical, thoracic, and sacral segments. Some of these neurons belong to the excitatory V2a interneurons and to plausible Renshaw cells, defined by the expression of Chx10 and calbindin, respectively. We also found that proprioceptive primary sensory neurons of type Ia2, Ia3, and Ib, defined by the expression of calbindin, calretinin, and Brn3c, respectively, provide presynaptic inputs to spinal Dmrt3 neurons. In addition, we demonstrated that Dmrt3 neurons receive inputs from brain areas involved in motor regulation, including the red nucleus, primary sensory–motor cortex, and pontine nuclei. In conclusion, adult spinal Dmrt3 neurons receive inputs from motor‐related brain areas as well as proprioceptive primary sensory neurons and have been shown to connect directly to motor neurons. Dmrt3 neurons are thus positioned to provide sensory–motor control and their connectivity is suggestive of the classical reflex pathways present in the spinal cord. [ABSTRACT FROM AUTHOR]

Neuronal circuits are essential components of the nervous system and determine various body functions. To understand how neuronal circuits operate it is necessary to identify the participating neuronal sub-populations and to dissect the function of the neurons at the molecular level. The locomotor central pattern generator that coordinates body movements is well suited for elucidating the assembly and identity of the participating neurons. Remarkable advances in the field of genetics are making studies in neuroscience more efficient and precise so that now, using nematode worms, fruit flies, zebrafish and mice as model organisms, a genetic approach can be used to identify molecules and neurons crucial for locomotor network functionality.

Ephrin-B3, a member of the ephrin family, has been found to be the midline barrier preventing corticospinal tract axons from recrossing. This allows for unilateral motor control. Animals lacking ephrin-B3 were generated to explore this issue. The mutant mice lacked unilateral motor control and hopped, having lost ability to move right and left limbs individually. It seems the binding of Eph14-bearing axonal processes to ephrin-B3 at the midline gives the repulsive signal that prevents corticospinal tract projections from recrossing the midline in the developing spinal cord.