Molecular Brain最新文献

Primary brain calcification (PBC) is a neurodegenerative disease that causes bilateral ectopic calcification in the brain. In this study, using newly generated Slc20a2 knockout (Slc20a2^-/-) mice, we establish an in vivo model for PBC. In contrast to heterozygous Slc20a2^+/- mice (9/9 animals) showing no obvious abnormalities, the homozygous Slc20a2^-/- mice exhibited severe calcification at 11 months of age (5/5 animals). Whilst smaller in size and number, the deposits were also detectable in 5-month-old Slc20a2^-/- mice (2/2 animals). By contrast, no obvious alterations were detectable in visceral organs, including the lung, kidney, liver, and spleen. Consistently, in PBC patients, despite the systemic mineral metabolic disturbance, calcification occurs only in a brain restricted manner. Hence, these observations suggest that our mouse model is capable of recapitulating certain aspects of human PBC etiology. In summary, our data suggested the utility of an in vivo PBC mouse model in understanding the pathological mechanisms behind brain calcification, which leads in development of novel therapeutics against PBC.

Substance P (SP) is a neuropeptide that functions in both the central and peripheral nervous systems. Although the peripheral actions of SP in regulating inflammatory responses have been extensively investigated, the effects of elevated peripheral SP on hippocampal functions such as spatial learning and memory remains unclear, even though SP can cross the blood-brain barrier. In this study, we found that male mice subcutaneously injected with SP for 14 days exhibited significant deficits in hippocampus-dependent memory, as assessed by the object place recognition and novel object recognition tests. In addition, long-term potentiation (LTP) at the hippocampal CA3-CA1 synapse was reduced in SP-treated mice. Transcriptomic analyses identified 77 differentially expressed genes (DEGs), and enrichment analysis highlighted pathways related to synaptic transmission, learning, and memory. These results suggest a novel skin-brain neuropeptide signaling axis. Targeting peripheral SP or its receptor may provide a therapeutic avenue for cognitive dysfunction associated with peripheral inflammation.

Parkinson's disease (PD) is recognized as the fastest-growing neurodegenerative disorder, impacting millions of individuals worldwide. It is primarily characterized by cardinal motor symptoms, including bradykinesia (slowness of movement), tremor, rigidity, and postural instability, which significantly impair the quality of life of those affected. Traditionally, the prevailing hypothesis has attributed these motor symptoms to the degeneration and subsequent loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Currently, emerging research suggests that this neuron-centric view may be overly simplistic and not entirely accurate. In light of this, growing attention has turned to the role of axons within the nigrostriatal pathway-an extensive network connecting the substantia nigra to the striatum, essential for both dopamine transmission and the overall functioning of the motor control by the brain. By directing a focus toward this aspect, in this nano review article we examine why nigrostriatal axons deserve increased attention and should be considered a pivotal target for further therapeutic strategies in PD.

Alpha-synuclein (α-synuclein), a key component of Lewy body pathology, is a classical hallmark of Parkinson's disease. In previous studies, our group has examined dopaminergic neuron-specific Atg7 autophagy-deficient mice, observing α-synuclein aggregation in vivo. This pathological process led to dopamine neuron loss and age-related motor impairments. Further, in a recent study, we developed a new mouse model by crossing human α-synuclein bacterial artificial chromosome transgenic mice with dopaminergic neuron-specific Atg7 conditional knockout mice to further investigate these mechanisms. These model mice exhibited accelerated Lewy body-like pathology and motor dysfunction, providing additional evidence that autophagy deficiency exacerbates synuclein toxicity in vivo. This nano-review provides essential clues that autophagy deficiency in dopamine neurons may contribute to the onset of human synuclein diseases.

We previously demonstrated that ibrutinib has therapeutic efficacy against AD pathologies when injected intraperitoneally at a lower dosage (10 mg/kg, daily for 2 weeks) or orally at a higher dosage (30 mg/kg, daily for 1 month) in AD mice models. However, the effect of chronic lower dose of ibrutinib by oral administration on AD pathologies has not been investigated yet. Therefore, we investigated whether long-term oral administration of ibrutinib at a lower dose (1 or 10 mg/kg, daily for 5 months) on AD pathology and in vivo toxicity in 5xFAD mice. We found ibrutinib enhanced cognitive function and alleviated Aβ pathology in 5xFAD mice without hepatotoxicity. Furthermore, ibrutinib-treated 5xFAD mice decrease tau hyperphosphorylation, p-GSK3α/β levels, and markers of neuroinflammation such as Iba-1, GFAP, and NLRP3. Collectively, these translational studies indicate chronic oral administration of ibrutinib at low doses improves cognitive function and suppresses AD pathology/neuroinflammation in an AD mice model thereby having potential as an effective multitarget AD therapeutic in clinical application.

Postoperative nausea and vomiting (PONV) after orthognathic surgery is a serious postoperative complication. The cholinergic receptor muscarinic 3 (CHRM3) rs2165870 and tachykinin receptor 1 (TACR1) rs3755468 single-nucleotide polymorphisms (SNPs) have been reported to be involved in PONV. We evaluated the impact of these SNPs on PONV in a Japanese population who underwent orthognathic surgery under PONV prophylaxis with the 5-hydroxytryptamine (serotonin) receptor 3A receptor antagonist ondansetron. In 121 patients, dexamethasone was administered after intubation, followed by ondansetron before the end of surgery. An 11-point numeric rating scale (NRS) score for PONV (0-2 h or 2-24 h after anesthesia endpoint [a.a.e.]) and the presence or absence of metoclopramide administration (0-2 h or 2-24 h a.a.e.) were evaluated. If patients complained of PONV and had an NRS score ≥ 4, then metoclopramide was administered intravenously for PONV rescue. Patients were genotyped for the CHRM3 rs2165870 and TACR1 rs3755468 SNPs, followed by the statistical analysis of associations between these SNPs and phenotypes. AA carriers of CHRM3 rs2165870 received metoclopramide at a significantly higher rate (P = 2.48 × 10^- 2) and had higher NRS scores (P = 3.40 × 10^- 2) under a diminished influence of ondansetron than GG and GA carriers. CC carriers of TACR1 rs3755468 had significantly higher NRS scores under the sufficient influence of ondansetron than CT and TT carriers (P = 9.97 × 10^- 3). Numeric rating scale scores showed a significant interaction between "time" (the effect of ondansetron) and "genotype" (two-way analysis of variance, P = 4.39 × 10^- 2). AA carriers of CHRM3 rs2165870 were significantly associated with "time" (P = 3.26 × 10^- 2), and CC carriers of TACR1 rs3755468 were not (P > 0.05). These results suggest that ondansetron significantly affects nausea that is associated with CHRM3, whereas it has a minimal effect on nausea that is associated with TACR1. This indicates that nausea that is associated with CHRM3 is qualitatively different from nausea that is associated with TACR1. Ondansetron mainly exerts its effects outside the blood-brain barrier, which may lead to differential impacts on nausea that is associated with CHRM3 and TACR1. These findings may provide future directions for tailor-made preventive measures against PONV that depend on high-risk genotypes of the CHRM3 rs2165870 and TACR1 rs3755468 SNPs.

The striatum is a critical component of the basal ganglia and plays a central role in regulating motor initiation and action selection. How cortical and subcortical inputs converging at the striatum regulate locomotion remains unclear. By examining gait changes in head-fixed mice running on a treadmill, we found that mice were capable of performing forward, but not backward, rhythmic locomotion using their forelimbs when the striatum and motor cortex were inactivated. The striatal activity is critical for adjusting initially disorganized gait to efficient rhythmic locomotion during forward running training, as well as for increasing the stride width during forward locomotion. The inputs from the motor cortex to striatum are important for the rhythmic locomotion, but not for changes of stride length and width during forward running training. In addition, D1 and D2 dopamine receptor activity in striatum are both important for efficient rhythmic locomotion, while exerting opposite effects on the stride width. Together, these results reveal multifactorial control of efficient and rhythmic gait by motor cortical and dopaminergic inputs converging at the striatum.

For social animals, social isolation is a potential threat to survival, and therefore can be considered innately aversive. Long-term social isolation induces a variety of social and affective deficits and has been used as a stress model in animal studies, with increasing insight into its underlying neural mechanisms. In contrast, short-term social isolation is known to elicit prosocial behaviors such as rebound social interactions, yet the neural basis of these adaptive responses remains poorly understood. Here, we investigated the effects of short-term social isolation on social and appetitive behaviors and examined the role of the insular cortex in modulating social preference in male mice. Three days of social isolation increased social contacts in a three-chamber social preference test. Additionally, socially isolated mice showed higher food intake in the home cage compared with the group-housed mice, and those exhibiting a higher social preference following social isolation also tended to consume more food during the isolation, postulating a potential correlation of social craving and food craving. Furthermore, chemogenetic suppression of the insular cortex during social isolation reduced rebound social interactions. We propose that the insular cortex modulates social valence by serving as an alert center for social deprivation. Our findings may help advance understanding of the neuronal mechanisms that underlie adaptive social and appetitive behaviors in response to social isolation.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by core symptoms including deficits in social interaction, repetitive and stereotyped behaviors, along with higher levels of anxiety and cognitive impairments. Previous studies demonstrate pronounced reduced density of calretinin (CR)-expressing GABAergic interneurons in both ASD patients and animal models. The object of the current study was to determine the role of CR in ASD-relevant behavioral aberrations. Herein, the mRNA and protein levels of CR in the prefrontal cortex (PFC) of mouse model of ASD based on prenatal exposure to valproic acid (VPA) were determined by qRT-PCR and Western blot analysis, respectively. Moreover, the behavioral abnormalities in naive mice with CR deficiency mediated by recombinant adeno-associated virus (rAAV) were evaluated in a comprehensive testing battery including social interaction, marble burying, self-grooming, open-field, elevated plus maze and novel object recognition tests. Furthermore, the action potential changes caused by CR deficiency were examined in neurons within the PFC in naive mouse. The results show that the mRNA and protein levels of PFC CR of VPA-induced mouse ASD model were reduced. Concomitantly, mice with CR knockdown displayed ASD-like behavioral aberrations, such as social impairments, elevated stereotypes, anxiety and memory defects. Intriguingly, patch-clamp recordings revealed that CR knockdown provoked decreased neuronal excitability by increasing action potential discharge frequencies together with decreased action potential threshold and rheobase. Our findings support a notion that CR knockdown might contribute to ASD-like phenotypes, with the pathogenesis most likely stemming from increased neuronal excitability.