The aggregation of TAR DNA binding protein 43 kDa (TDP-43) is related to different neurodegenerative diseases, which leads to microglial activation and neuronal loss. The molecular mechanism driving neuronal death by reactive microglia, however, has not been completely resolved. In this study, we generated a mouse model by overexpressing mutant human TDP-43 (M337V) in the primary motor cortex, leading to prominent motor-learning deficits. In vivo 2-photon imaging shows an active approach of microglia toward parvalbumin interneurons, resulting in disrupted cortical excitatory-inhibitory balance. Proteomics studies suggest that activation of the complement pathway induces microglial activity. To develop an early interventional strategy, treadmill exercise successfully prevents the deterioration of motor dysfunction under enhanced adipocytic release of clusterin to block the complement pathway. These results demonstrate a previously unrecognized pathway by which TDP-43 induces cortical deficits and provide additional insights for the mechanistic explanation of exercise training in disease intervention.

Salt homeostasis is orchestrated by both neural circuits and peripheral endocrine factors. The colon is one of the primary sites for electrolyte absorption, while its potential role in modulating sodium intake remains unclear. Here, we revealed that a gastrointestinal hormone, secretin, is released from colon endocrine cells under body sodium deficiency and is indispensable for inducing salt appetite. As the neural substrate, circulating secretin activates specific receptors in the nucleus of the solitary tracts, which further activates the downstream paraventricular nucleus of the hypothalamus, resulting in enhanced sodium intake. These results demonstrated a previously unrecognized gut-brain pathway for the timely regulation of sodium homeostasis.

Inactivation of Celsr3 in the forebrain results in defects of longitudinal axonal tracts such as the corticospinal tract. In this study, we inactivated Celsr3 in the brainstem using En1-Cre mice (Celsr3 cKO) and analyzed axonal and behavioral phenotypes. Celsr3 cKO animals showed an 83% reduction of rubrospinal axons and 30% decrease of corticospinal axons in spinal segments, associated with increased branching of dopaminergic fibers in the ventral horn. Decreases of spinal motoneurons, neuromuscular junctions, and electromyographic signal amplitude of the biceps were also found in mutant animals. Mutant mice had impaired motor coordination and defective response to heavy mechanical stimulation, but no disability in walking and food pellet handling. Transsynaptic tracing demonstrated that rubrospinal axons synapse on spinal neurons in the deep layer of the dorsal horn, and mechanical stimulation of hindpaws induced strong calcium signal of red nuclei in control mice, which was less prominent in mutant mice. In conclusion, Celsr3 regulates development of spinal descending axons and the motor network in cell and non-cell autonomous manners, and the maturation of the rubrospinal system is required for motor coordination and response to mechanical stimulation.

In mammals, thirst is strongly influenced by the subfornical organ (SFO), a forebrain structure that integrates circulating signals including osmotic pressure and sodium contents. Secretin (SCT), a classical gastrointestinal hormone, has been implicated as a humoral factor regulating body-fluid homeostasis. However, the neural mechanism of secretin in the central nervous system in managing thirst remains unclear. In this study, we report that the local ablation of SCT receptor (SCTR) in the SFO reduces water but not salt intake in dehydrated mice and this effect could not be rescued by exogenous SCT administration. Electrophysiology with single-cell RT-PCR indicates that SCT elicits inward currents in the SFO neuronal nitric oxide synthase (SFOnNOS) neurons via SCTR in the presence of glutamate receptor antagonists. We further show that the SCTR in the SFO permits the activation of SFOnNOS neurons under distinct thirst types. Projection-specific gene deletion of SCTR in SFO to the median preoptic nucleus (MnPO) pathway also reduces water intake in dehydrated animals. SCT signaling thus plays an indispensable role in driving thirst. These data not only expand the functional boundaries of SCTR but also provide insights into the central mechanisms of homeostatic regulation.