The hippocampal dorsal CA2 subregion (dCA2) is critical for social memory; however, its contribution to other types of hippocampus-dependent memories is not well understood. Here, we performed dCA2-specific circuit tracing, single-neuron projectome analysis, photometric Ca2+ imaging, and optogenetic manipulations to study the physiological roles of dCA2 neurons and their axon projections in behavioral paradigms for novel object recognition, novel location recognition, and contextual fear memory. We found that dCA2 neurons sent their strongest axon projections to the dorsal portion of ventral CA1 (vCA1d) and showed object and location-specific Ca2+ responses. Notably, the dCA2-vCA1d projection contributed to the memory formation of object location but not identity. Furthermore, optogenetic inhibition of the dCA2-vCA1d axon terminals reduced fear responses to foot shocks and impaired contextual memory formation. Collectively, our study reveals critical roles of the dCA2-vCA1d circuit in spatial and context-dependent memories, providing new insights into the function of CA2 neurons.

Neuropathic pain is frequently comorbidity with cognitive deficits. Neuralized1 (Neurl1)-mediated ubiquitination of CPEB3 in the hippocampus is critical in learning and memory. However, the role of Neurl1 in the cognitive impairment in neuropathic pain remains elusive. Herein, we found that lumbar 5 spinal nerve ligation (SNL) in male rat-induced neuropathic pain was followed by learning and memory deficits and LTP impairment in the hippocampus. The Neurl1 expression in the hippocampal CA1 was decreased after SNL. And this decrease paralleled the reduction of ubiquitinated-CPEB3 level and reduced production of GluA1 and GluA2. Overexpression of Neurl1 in the CA1 rescued cognitive deficits and LTP impairment, and reversed the reduction of ubiquitinated-CPEB3 level and the decrease of GluA1 and GluA2 production following SNL. Specific knockdown of Neurl1 or CPEB3 in bilateral hippocampal CA1 in naïve rats resulted in cognitive deficits and impairment of synaptic plasticity. The rescued cognitive function and synaptic plasticity by the treatment of overexpression of Neurl1 before SNL were counteracted by the knockdown of CPEB3 in the CA1. Collectively, the above results suggest that the downregulation of Neurl1 through reducing CPEB3 ubiquitination and, in turn, repressing GluA1 and GluA2 production and mediating synaptic plasticity impairment in hippocampal CA1 leads to the genesis of cognitive deficits in neuropathic pain.

Bayesian integration is posited as a fundamental computational mechanism underlying multisensory integration, and feedforward neural networks have been proposed to instantiate optimal Bayesian integration (OBI). However, empirical and theoretical research highlights the prevalence of neural feedback projections, raising questions about how recurrent neural networks might contribute to multisensory OBI. We simulated a two-layer neural circuit computational model with reciprocal projections performing a perceptual discrimination task, in which sensory inputs comprise single or dual modalities. The model with reciprocal projections between sensory and decision-making modules can match, underperform, or outperform OBI, depending on feedforward-feedback interplay. This model performance variability accords with prior experimental data. In addition, our theoretical analysis reveals the importance of non-linear interactions within neuronal assemblies in mediating such multisensory integration behaviors. Our work suggests that sensory modalities can be entangled through top-down feedback, challenging the traditional view of their independence, while explaining deviations from OBI.

Early social isolation (SI) impairs social ability, which can be partially rescued after resocialization, but the underlying mechanisms have been rarely addressed. This study reported that adolescent SI mice resocialized with group housing (GH) mice, but not with SI mice, showed improved social behavior performances, increased myelination in the medial prefrontal cortex (mPFC), and upregulated Egr2 expression in oligodendrocytes (OLs). Specific down-regulation of OL Egr2 in GH companions or overexpression of OL Egr2 in SI peers abolished or rescued their repair effects on mPFC hypomyelination and social ability defects in SI mice, respectively. Furthermore, the improving effect of GH companions on OL Egr2 expression and myelinogenesis in the mPFC of SI mice was abolished when GH mice were treated with corticosterone. RNA-sequencing analysis showed that Egr2 enhanced myelination by inhibiting PDGFRα. Together, these results revealed that the Egr2/PDGFRα axis mediates distinct peer effects in rescuing SI-induced hypomyelination and social ability impairment.

Ubiquinol cytochrome c reductase core protein I (UQCRC1) is a crucial subunit of Complex III, essential for its assembly. Reduced UQCRC1 expression impairs memory and spatial learning in mice, though the mechanisms are unclear. This study found that diminished UQCRC1 expression resulted in significant impairments in hippocampus-dependent cognition, which correlated with a notable decrease in UQCRC1 and synaptic proteins within the dentate gyrus (DG). RNA sequencing analysis of the hippocampus revealed a reduction in cilia, identified as a critical factor contributing to these cognitive deficits. Significantly, the overexpression of Ttbk2 in the DG restored ciliary function and mitigated cognitive impairments. Additionally, in vivo electrophysiological experiments demonstrated that theta and gamma rhythms and wide-wave interneuron reactivity in the hippocampus DG were present in Uqcrc1+/- mice and could be rescued through Ttbk2 overexpression. These findings suggest that the downregulation of UQCRC1 expression contributes to cognitive decline by impairing neural oscillations and the functionality of wide-wave interneurons, likely due to ciliary damage.

Cerebral edema is characterized by fluid accumulation, and the glymphatic system (GS) plays a pivotal role in regulating fluid transport. Using the Tenecteplase system, magnesium salt of salvianolic acid B/ginsenoside Rg1 (SalB/Rg1) was injected intravenously into mice 4.5 h after middle cerebral artery occlusion and once every 24 h for the following 72 h. GS function was assessed by Evans blue imaging, near-infrared fluorescence region II (NIR-II) imaging, and magnetic resonance imaging (MRI). SalB/Rg1 had significant effects on reducing the infarct volume and hemorrhagic transformation score, improving neurobehavioral function, and protecting tissue structure, especially inhibiting cerebral edema. Meanwhile, the influx/efflux drainage of GS was enhanced by SalB/Rg1 according to NIR-II imaging and MRI. SalB/Rg1 inhibited matrix metalloproteinase-9 (MMP-9) activity, reduced cleaved β-dystroglycan (β-DG), and stabilized aquaporin-4 (AQP4) polarity, which was verified by colocalization with CD31. Our findings indicated that SalB/Rg1 treatment enhances GS function and attenuates cerebral edema, accompanying the regulation of the MMP9/β-DG/AQP4 pathway.

The mammalian cochlea relies on outer and inner hair cells (OHCs/IHCs) for sound amplification and signal transmission. Rab3-interacting molecular binding protein 2 (RIMBP2), expressed in receptor cells and neurons at synaptic active zones, remains poorly characterized in hearing. We therefore generated a Rimbp2 knockout (KO) mouse model (Rimbp2-/-), which exhibited severe hearing loss with elevated thresholds, prolonged latencies, and reduced amplitudes in auditory brainstem response Wave I. OHC loss via apoptosis was correlated with threshold elevation. In IHCs, patch-clamp recordings revealed reduced exocytosis, including a diminished readily-releasable pool, impaired sustained release, and blocked fast endocytosis. Immunostaining showed unchanged ribbon synapse numbers but positional shifts in the basal pole of KO IHCs. These findings demonstrated RIMBP2's essential role in OHC survival and its broader regulatory functions in IHC synaptic transmission than previously recognized.

Vestibular hair cells (HCs) in the inner ear, crucial for balance and spatial orientation, are classified into type I and type II subtypes, but the mechanisms regulating their differentiation remain unclear. In this study, we examined the role of Pou4f3, an important transcription factor, in vestibular HC differentiation using Pou4f3DTR/DTR (deficient) and Pou4f3CreER/CreER (knockout) mouse models. In Pou4f3-deficient mice, the HC number decreased, and immature HCs failed to develop type I characteristics, indicating a developmental arrest. While type II HCs differentiated normally, Pou4f3 deficiency disrupted HC bundle formation and cell polarity. Findings from knockout models further confirmed the essential role of Pou4f3 in vestibular HC subtype specification. This study underscores the critical role of Pou4f3 in determining vestibular HC subtypes and offers insights into potential strategies for restoring vestibular function through HC regeneration.

Cisplatin is a widely-used chemotherapeutic agent, but its dose-limiting ototoxicity often results in irreversible hearing loss. The pathogenesis involves oxidative stress, apoptosis, DNA damage, and inflammatory responses, yet effective preventive strategies remain limited. Here, we demonstrate that magnesium hydride (MgH2), a hydrogen-releasing compound, provides robust protection against cisplatin-induced hearing loss. Our results showed that MgH2 protected auditory function and preserved cochlear hair cells in vivo. Furthermore, it significantly attenuated cisplatin-induced oxidative stress and apoptosis in cultured HEI-OC1 (House Ear Institute-Organ of Corti 1) cells and cochlear explants. Notably, MgH2 suppressed NOD-like receptor family pyrin domain containing 3 (NLRP3)-mediated inflammatory cascades, thereby limiting downstream inflammatory damage. These findings revealed that MgH2 alleviated cisplatin-induced hearing loss through integrated antioxidant, anti-inflammatory, and anti-apoptotic pathways, with NLRP3 identified as a critical regulatory molecule. Collectively, our study provides compelling evidence for MgH2 as a potential therapeutic candidate for the prevention of cisplatin-induced hearing loss.

Social working memory (SWM)-the ability to maintain and manipulate social information in the brain-plays a crucial role in social interactions. However, research on SWM is still in its infancy and is often treated as a unitary construct. In the present study, we propose that SWM can be conceptualized as having two relatively independent components: "externally oriented SWM" (e-SWM) and "internally oriented SWM" (i-SWM). To test this external-internal hypothesis, participants were tasked with memorizing and ranking either facial expressions (e-SWM) or personality traits (i-SWM) associated with images of faces. We then examined the neural correlates of these two SWM components and their functional roles in empathy. The results showed distinct activations as the e-SWM task activated the postcentral and precentral gyri while the i-SWM task activated the precuneus/posterior cingulate cortex and superior frontal gyrus. Distinct multivariate activation patterns were also found within the dorsal medial prefrontal cortex in the two tasks. Moreover, partial least squares analyses combining brain activation and individual differences in empathy showed that e-SWM and i-SWM brain activities were mainly correlated with affective empathy and cognitive empathy, respectively. These findings implicate distinct brain processes as well as functional roles of the two types of SWM, providing support for the internal-external hypothesis of SWM.