Intracellular magnesium optimizes transmission efficiency and plasticity of hippocampal synapses by reconfiguring their connectivity.

Synapses at dendritic branches exhibit specific properties for information processing. However, how the synapses are orchestrated to dynamically modify their properties, thus optimizing information processing, remains elusive. Here, we observed at hippocampal dendritic branches diverse configurations of synaptic connectivity, two extremes of which are characterized by low transmission efficiency, high plasticity and coding capacity, or inversely. The former favors information encoding, pertinent to learning, while the latter prefers information storage, relevant to memory. Presynaptic intracellular Mg2+ crucially mediates the dynamic transition continuously between the two extreme configurations. Consequently, varying intracellular Mg2+ levels endow individual branches with diverse synaptic computations, thus modulating their ability to process information. Notably, elevating brain Mg2+ levels in aging animals restores synaptic configuration resembling that of young animals, coincident with improved learning and memory. These findings establish intracellular Mg2+ as a crucial factor reconfiguring synaptic connectivity at dendrites, thus optimizing their branch-specific properties in information processing.

Amino acid formula induces microbiota dysbiosis and depressive-like behavior in mice.

Amino acid formula (AAF) is increasingly consumed in infants with cow's milk protein allergy; however, the long-term influences on health are less described. In this study, we established a mouse model by subjecting neonatal mice to an amino acid diet (AAD) to mimic the feeding regimen of infants on AAF. Surprisingly, AAD-fed mice exhibited dysbiotic microbiota and increased neuronal activity in both the intestine and brain, as well as gastrointestinal peristalsis disorders and depressive-like behavior. Furthermore, fecal microbiota transplantation from AAD-fed mice or AAF-fed infants to recipient mice led to elevated neuronal activations and exacerbated depressive-like behaviors compared to that from normal chow-fed mice or cow's-milk-formula-fed infants, respectively. Our findings highlight the necessity to avoid the excessive use of AAF, which may influence the neuronal development and mental health of children.

Multi-region calcium imaging in freely behaving mice with ultra-compact head-mounted fluorescence microscopes.

To investigate the circuit-level neural mechanisms of behavior, simultaneous imaging of neuronal activity in multiple cortical and subcortical regions is highly desired. Miniature head-mounted microscopes offer the capability of calcium imaging in freely behaving animals. However, implanting multiple microscopes on a mouse brain remains challenging due to space constraints and the cumbersome weight of the equipment. Here, we present TINIscope, a Tightly Integrated Neuronal Imaging microscope optimized for electronic and opto-mechanical design. With its compact and lightweight design of 0.43 g, TINIscope enables unprecedented simultaneous imaging of behavior-relevant activity in up to four brain regions in mice. Proof-of-concept experiments with TINIscope recorded over 1000 neurons in four hippocampal subregions and revealed concurrent activity patterns spanning across these regions. Moreover, we explored potential multi-modal experimental designs by integrating additional modules for optogenetics, electrical stimulation or local field potential recordings. Overall, TINIscope represents a timely and indispensable tool for studying the brain-wide interregional coordination that underlies unrestrained behaviors.

NEATmap: a high-efficiency deep learning approach for whole mouse brain neuronal activity trace mapping.

Quantitative analysis of activated neurons in mouse brains by a specific stimulation is usually a primary step to locate the responsive neurons throughout the brain. However, it is challenging to comprehensively and consistently analyze the neuronal activity trace in whole brains of a large cohort of mice from many terabytes of volumetric imaging data. Here, we introduce NEATmap, a deep learning-based high-efficiency, high-precision and user-friendly software for whole-brain neuronal activity trace mapping by automated segmentation and quantitative analysis of immunofluorescence labeled c-Fos+ neurons. We applied NEATmap to study the brain-wide differentiated neuronal activation in response to physical and psychological stressors in cohorts of mice.

Cellular and circuit architecture of the lateral septum for reward processing.

The lateral septum (LS) is composed of heterogeneous cell types that are important for various motivated behaviors. However, the transcriptional profiles, spatial arrangement, function, and connectivity of these cell types have not been systematically studied. Using single-nucleus RNA sequencing, we delineated diverse genetically defined cell types in the LS that play distinct roles in reward processing. Notably, we found that estrogen receptor 1 (Esr1)-expressing neurons in the ventral LS (LSEsr1) are key drivers of reward seeking via projections to the ventral tegmental area, and these neurons play an essential role in methamphetamine (METH) reward and METH-seeking behavior. Extended exposure to METH increases the excitability of LSEsr1 neurons by upregulating hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, thereby contributing to METH-induced locomotor sensitization. These insights not only elucidate the intricate molecular, circuit, and functional architecture of the septal region in reward processing but also reveal a neural pathway critical for METH reward and behavioral sensitization.