Mol Brain [JOURNAL]
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200 papers
Identification of VGLUT3-expressing LTMRs-recruited spinal circuits for itch inhibition.
Su X, Wang L, Liu X … +1 more , Zhang Y
Mol Brain · 2025 Sep · PMID 41029777 · Full text
Itch is a common symptom among patients suffering dermatological and systemic diseases, yet effective clinical treatments are currently lacking. Previous research has suggested that vesicular glutamate transporter 3 (VGL...
Itch is a common symptom among patients suffering dermatological and systemic diseases, yet effective clinical treatments are currently lacking. Previous research has suggested that vesicular glutamate transporter 3 (VGLUT3)-lineage sensory neurons may play a role in inhibiting itch, but the circuit mechanisms within the spinal cord remain unclear. In this study, we employed optogenetic techniques to activate VGLUT3-lineage sensory afferents in mice and observed a significant reduction in scratching behaviors elicited by both pruritogens and mechanical stimuli. Moreover, aversive component of chemical itch assessed by conditioned place aversion (CPA) was abrogated. Viral tracing combined with electrophysiological recordings revealed synaptic connections between VGLUT3 sensory neurons and spinal dynorphin (SC) /neuropeptide Y-expressing (SC) neurons. Further pharmacological studies indicated that intrathecal injection of antagonists of neuropeptide Y1 receptor and kappa opioid receptor (KOR) separately diminished VGLUT3 neurons-mediated inhibitory effects on mechanical and chemical itch, respectively. In summary, our findings suggest that VGLUT3 sensory neurons participate in itch regulation through interactions with two classes of inhibitory neurons in the spinal cord, shedding light on potential therapeutic targets for distinct forms of itch management.
Analgesic effects of transcutaneous auricular vagus nerve stimulation on partial sciatic nerve ligation-induced neuropathic pain in mice via serotonergic pathways.
Shin H, Choi S, Chung G … +1 more , Kim SK
Mol Brain · 2025 Sep · PMID 41013640 · Full text
Current treatments for neuropathic pain often provide limited relief and are associated with significant side effects. Transcutaneous auricular vagus nerve stimulation (taVNS) shows promise as a non-pharmacological analg...
Current treatments for neuropathic pain often provide limited relief and are associated with significant side effects. Transcutaneous auricular vagus nerve stimulation (taVNS) shows promise as a non-pharmacological analgesic approach; however, its optimal therapeutic configuration and underlying brain mechanisms remain incompletely understood. This study investigated the analgesic effects of taVNS on neuropathic pain in a mouse model induced by partial sciatic nerve ligation (PSL), exploring mechanisms and optimizing configurations. PSL-induced neuropathic pain in mice, characterized by mechanical allodynia, was significantly alleviated by taVNS. The most robust analgesic effects were observed with multiple bilateral taVNS sessions, administered once daily for three consecutive days, with effects persisting for at least 48 h post-stimulation. Immunohistochemical analysis of c-Fos expression revealed that taVNS increased neural activity in the dorsal raphe nucleus (DRN), a key source of serotonin, while simultaneously reducing activity in the central amygdala (CeA), a region critical for pain processing and affective responses. Further experiments demonstrated that the analgesic effects of taVNS were abolished by systemic administration of p-chlorophenylalanine, an inhibitor of serotonin synthesis. These findings underscore the critical role of serotonin signaling in mediating taVNS-induced analgesia for neuropathic pain. The study also highlights the importance of stimulation parameters, identifying a multiple bilateral configuration as particularly effective. Our results suggest that taVNS, potentially acting via the DRN-serotonergic system to modulate limbic structures like the CeA, holds significant potential as a non-pharmacological therapeutic option for managing neuropathic pain.
Voluntary running improves synaptic degeneration of the anterior cingulate cortex in knee osteoarthritis.
Miyake R, Yamanaka M, Taniguchi W … +6 more , Nishio N, Matsuyama Y, Ueno T, Kaimochi Y, Nakatsuka T, Yamada H
Mol Brain · 2025 Aug · PMID 40847348 · Full text
Osteoarthritis of the knee (knee OA) causes chronic pain involving peripheral tissues, the spinal cord, and the brain. Neuropathic pain leads to changes in synaptic plasticity in the anterior cingulate cortex (ACC). Howe...
Osteoarthritis of the knee (knee OA) causes chronic pain involving peripheral tissues, the spinal cord, and the brain. Neuropathic pain leads to changes in synaptic plasticity in the anterior cingulate cortex (ACC). However, whether such changes occur in knee OA mice and their association with exercise therapy remains unclear. Therefore, this study investigated these aspects using electrophysiological and behavioral approaches. We found no induction of pre- or post-long-term potentiation (LTP) in the ACC of knee OA mice. Application of ZD7288 and zeta inhibitory peptide (ZIP) reduced the amplitude of evoked excitatory postsynaptic currents, indicating pre-existing changes in synaptic plasticity in the ACC. Microinjection of ZD7288 and ZIP improved pain-escape and anxiety-like behaviors. Voluntary running exercise induced pre- and post-LTP and improved these behaviors in knee OA mice. Exercise therapy for knee OA may alter synaptic plasticity in the ACC, contributing to behavioral improvements.
Comprehensive behavioral phenotyping of male Septin 3-deficient mice reveals task-specific abnormalities.
Ageta-Ishihara N, Takao K, Miyakawa T … +1 more , Kinoshita M
Mol Brain · 2025 Aug · PMID 40846958 · Full text
The septin cytoskeleton is recognized as the fourth component of the cytoskeleton. Septin 3 (SEPT3)/G-septin is a neuron-selective subunit of the septin family and is widely expressed in mature neurons. We previously dem...
The septin cytoskeleton is recognized as the fourth component of the cytoskeleton. Septin 3 (SEPT3)/G-septin is a neuron-selective subunit of the septin family and is widely expressed in mature neurons. We previously demonstrated that SEPT3 regulates long-term potentiation (L-LTP)-dependent extension of smooth endoplasmic reticulum (sER) into dendritic spines of granule cells in the hippocampal dentate gyrus (DG), and that Sept3 knockout (Sept3−/−) mice exhibited impairments in DG-dependent spatial long-term memory. However, the broader behavioral consequences of SEPT3 deficiency remain largely unexplored. To address this, we conducted comprehensive behavioral phenotyping of male Sept3−/− mice using a standardized test battery. In the social interaction test in a novel environment, Sept3−/− mice showed increased contact frequency and interaction time. In contrast, performance in the three-chamber social interaction test was comparable to wild-type mice, indicating context-dependent deficits. In contextual fear conditioning, Sept3−/− mice displayed reduced freezing 24 h after training, but not 35 days later. In the T-maze forced alternation task, deficits were observed in choice accuracy and latency. These results demonstrate that Sept3−/− mice exhibit selective behavioral impairments depending on task demands and environmental context. Our findings provide the first behavioral characterization of Sept3−/− mice and offer new insights into the functional role of SEPT3, laying a foundation for future investigation into its molecular and circuit-level mechanisms.
Generation of a new Slc20a2 knockout mouse line as in vivo model for primary brain calcification.
Kurita H, Kitaura H, Nishii K … +6 more , Masaka T, Ohuchi K, Inden M, Kakita A, Osawa M, Hozumi I
Mol Brain · 2025 Aug · PMID 40836304 · Full text
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 mod...
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.
Peripheral substance P induces deficits in hippocampal synaptic plasticity and memory.
Kim SY, Yoon KN, Ji J … +9 more , Kim MG, Choi SA, Park G, Lee WW, Chung JH, Kim SJ, An JY, Lee DH, Lee YS
Mol Brain · 2025 Aug · PMID 40818973 · Full text
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 eff...
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.
Neurodegeneration in Parkinson's disease: are we looking at the right spot?
Rocha GS, Freire MAM, Falcao D … +3 more , Outeiro TF, Lima RR, Santos JR
Mol Brain · 2025 Aug · PMID 40751268 · Full text
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 (slo...
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.
Correction to: Synergistic actions of corticosterone and BDNF on rat hippocampal LTP.
Thacker JS, Ralph LT, Koek L … +6 more , Abbasian A, Bettio LB, Smith AE, Georgiou J, Christie BR, Collingridge GL
Mol Brain · 2025 Jul · PMID 40708024 · Full text
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Unraveling the mystery: How autophagy deficiency in dopaminergic neurons drives human Parkinson's disease.
Noda S, Hattori N
Mol Brain · 2025 Jul · PMID 40708000 · Full text
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 mic...
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.
Chronic oral administration of ibrutinib prevents long-term memory deficits and reduces AD pathology and neuroinflammatory responses in a mouse model of AD.
Lee HJ, Kang S, Jeong YJ … +7 more , Park JH, Hwang JW, Gu CH, Jung TM, Oh S, Jang JY, Hoe HS
Mol Brain · 2025 Jul · PMID 40696386 · Full text
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...
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.
Differential effects of antiemetic serotonin receptor antagonist Ondansetron on nausea associated with CHRM3 rs2165870 and TACR1 rs3755468 single-nucleotide polymorphisms.
Kang Y, Ohka S, Nishizawa D … +6 more , Hasegawa J, Nakayama K, Yoshida K, Koshika K, Ichinohe T, Ikeda K
Mol Brain · 2025 Jul · PMID 40691854 · Full text
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-nucl...
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) and had higher NRS scores (P = 3.40 × 10) 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). 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). AA carriers of CHRM3 rs2165870 were significantly associated with "time" (P = 3.26 × 10), 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 regulation of rhythmic locomotion by motor cortical and dopaminergic inputs in the mouse striatum.
Zhang H, Su Y, Wu X … +1 more , Gan WB
Mol Brain · 2025 Jul · PMID 40671088 · Full text
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 r...
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.
Modulation of social valence by insular cortex activity during acute social isolation in mice.
Hiyoshi K, Matsushita D, Watabe AM
Mol Brain · 2025 Jul · PMID 40665452 · Full text
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 a...
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.
Deficiency of calretinin in prefrontal cortex causes behavioral deficits relevant to autism spectrum disorder in mice.
Zhang Y, Zhao X, Gao C … +7 more , Shi S, Chen M, Guo B, Hu S, Mei D, Duan X, Wang X
Mol Brain · 2025 Jul · PMID 40652246 · Full text
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 cogni...
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.
Role of autophagy in neurotoxic protein's clearance following post-ischemic stroke: where we are and what we know?
Kazmi S, Farokhi-Sisakht F, Davoody S … +5 more , Bahlakeh G, Abbaszadeh F, Rahbarghazi R, Shekarchi A, Karimipour M
Mol Brain · 2025 Jul · PMID 40629391 · Full text
BACKGROUND: The role of autophagy following stroke and its underlying cascades have not yet been investigated in detail. The ischemic brain is characterized by complex pathophysiological mechanisms, including increased e...
BACKGROUND: The role of autophagy following stroke and its underlying cascades have not yet been investigated in detail. The ischemic brain is characterized by complex pathophysiological mechanisms, including increased excitotoxicity, oxidative stress, inflammatory responses, intrinsic and extrinsic apoptotic pathways, blood-brain barrier (BBB) integrity, neurotoxic proteins, and neurodegeneration. By engaging multiple molecular pathways, autophagy plays both protective and detrimental roles in ischemic stroke. Main text: This review explores the state-of-the-art regarding autophagy’s role in neurotoxic protein clearance, neuroinflammation, oxidative stress, BBB, and neural tissue regeneration during and after ischemic stroke. Additionally, neuroinflammation is modulated by autophagy such that the inflammasomes and proinflammatory complexes that cause post-ischemic neuroinflammation are degraded. However, autophagy can be dysregulated, resulting in chronic neuro-inflammation. Moreover to counteract the excessive oxidative stress, autophagy is triggered mainly through the PINK1/Parkin pathway. In contrast, over-activated autophagy may cause neuronal damage and cell death. Autophagy maintains BBB integrity by restoring tight junction proteins. However, if dysregulated, the infiltration of inflammatory neurotoxic substances can exacerbate ischemic injury, highlighting the need for balanced regulation of autophagy. As the central nervous system (CNS) has limited regenerative capability, neural stem and progenitor cells are activated to promote neurogenesis following stroke. Autophagy can also enhance those regenerative processes. Conclusions Modulating autophagy offers potential therapeutic strategies in stroke patients by enhancing the protective effects of autophagy while minimizing its harmful consequences.
Repeated naloxone-induced morphine withdrawal alters blood brain barrier and blood spinal cord barrier integrity in mice.
Kohro Y, Brown CE, Trang T
Mol Brain · 2025 Jul · PMID 40624697 · Full text
Passage of molecules across the central nervous system is tightly regulated by the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB), which restrict entry of many substances, including opioid medications. He...
Passage of molecules across the central nervous system is tightly regulated by the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB), which restrict entry of many substances, including opioid medications. Here, we examined the effects of opioid withdrawal on BBB and BSCB integrity by measuring extravascular levels of peripherally injected dyes - Evans Blue (high molecular weight) and sodium fluorescein (NaFl, low molecular weight) - in the brain and spinal cord. In morphine-dependent male and female mice, repeated naloxone challenge induced robust withdrawal behaviors concomitant with region specific dye extravasation. In a fixed dose morphine paradigm, Evans Blue extravasation was highest within the cortex, hippocampus, cerebellum, and brainstem (pons and medulla) in male mice, and in the hypothalamus in female mice. By contrast, NaFl extravasation remained unchanged in both sexes. In an escalating dose morphine paradigm, Evans Blue extravasation was most prominent in the brainstem (pons and medulla) of both sexes, as well as in the lumbar of male mice and cervical spinal cord of female mice. NaFl extravasation in these regions was unchanged in male but reduced in female mice. These findings suggest that repeated opioid withdrawal alters permeability of the BBB and BSCB in discrete regions of the brain and spinal cord.
Multi-omics integration reveals the role of N6-methyladenosine in epilepsy, ischemic stroke, and vascular dementia.
Zhang X, Xu Y, Hu H … +3 more , Liao Z, Lou C, Zou X
Mol Brain · 2025 Jul · PMID 40624693 · Full text
BACKGROUND: N6-methyladenosine (m6A) methylation is an essential epigenetic modification that regulates mRNA stability, splicing, and translation. Its role in neurological diseases, including epilepsy, ischemic stroke, a...
BACKGROUND: N6-methyladenosine (m6A) methylation is an essential epigenetic modification that regulates mRNA stability, splicing, and translation. Its role in neurological diseases, including epilepsy, ischemic stroke, and vascular dementia (VaD), remains poorly understood. METHODS: We integrated multi-omics data, including GWAS, m6A quantitative trait loci (QTL), expression QTL (eQTL), and protein QTL (pQTL), and using FUSION to assess the association of m6A with these diseases. Transcriptome-wide association studies (TWAS) and Mendelian Randomization (MR) were performed to identify causal relationships between m6A sites, gene expression, and disease. Differentially expressed genes (DEGs) were analyzed via RNA sequencing and enriched for biological pathways. Protein-protein interaction (PPI) networks and m6A-related gene-disease associations were constructed to reveal regulatory mechanisms. RESULTS: We identified 218 m6A sites significantly associated with the three diseases, highlighting 3,430 associations between m6A sites and gene expression. Functional enrichment analysis revealed key pathways, including base excision repair and chemokine-mediated signaling. MR analysis identified causal relationships, such as NBL1 in epilepsy, TPGS2 in ischemic stroke, and SERINC2 in VaD. PPI analysis revealed interactions involving critical proteins like PARP1, MCL1, and CD40, underscoring their role in neuroinflammation and apoptosis. CONCLUSION: Our findings elucidate the genetic and epigenetic roles of m6A in epilepsy, ischemic stroke, and VaD, uncovering potential mechanisms by which m6A modulates gene and protein expression to influence disease outcomes. These insights highlight m6A as a promising biomarker and therapeutic target for neurological diseases.
Visualization of the existence of LEAP2 in the nucleus accumbens and its role in amphetamine-induced locomotor activity.
Lee S, Yoo GY, Yoon HS … +1 more , Kim JH
Mol Brain · 2025 Jul · PMID 40611288 · Full text
The nucleus accumbens (NAcc) is a key brain region in reward circuitry, mediating responses to psychostimulants, such as amphetamine (AMPH), including locomotor activity. This effect is known to be enhanced by the orexig...
The nucleus accumbens (NAcc) is a key brain region in reward circuitry, mediating responses to psychostimulants, such as amphetamine (AMPH), including locomotor activity. This effect is known to be enhanced by the orexigenic neuropeptide ghrelin acting through growth hormone-secretagogue receptors (GHSR) expressed in the region. Recently, liver-expressed antimicrobial peptide 2 (LEAP2) was identified as another ligand for GHSR that opposes ghrelin's action. Based on its antagonism, we hypothesized that LEAP2 modulates AMPH-induced locomotor activity in the NAcc. To examine this, we first confirmed the presence of LEAP2 protein in this NAcc and observed that its fluorescent signals were predominantly localized in neurons, including medium spiny neurons (MSNs). We then investigated whether LEAP2 microinjection alters AMPH-induced locomotor activity. Our findings showed that LEAP2 inhibited acute AMPH-induced locomotor activity in a dose-dependent manner. However, its inhibitory effects were absent following chronic AMPH exposure, indicating that the effect of LEAP2 on AMPH-induced locomotor activity varies depending on drug-exposed physiological status. These results provide new insights into a state-dependent regulatory role of LEAP2 in AMPH-induced locomotor activity.
CSF Amyloid-β42 associates with neuropsychiatric and cognitive outcomes via cerebral glucose metabolism.
Azargoonjahromi A, Nasiri H, Alzheimer’s Disease Neuroimaging Initiative#
Mol Brain · 2025 Jul · PMID 40597399 · Full text
Amyloid-β42 (Aβ42) regulates synaptic plasticity and memory formation at physiological levels in the brain, but in Alzheimer's disease (AD), it can disrupt brain function and glucose metabolism. This disruption contribut...
Amyloid-β42 (Aβ42) regulates synaptic plasticity and memory formation at physiological levels in the brain, but in Alzheimer's disease (AD), it can disrupt brain function and glucose metabolism. This disruption contributes to cognitive decline and neuropsychiatric symptoms, highlighting the need to better understand its complex effects. This study investigated the associations among cerebrospinal fluid (CSF) Aβ42 levels, cerebral glucose metabolism (assessed via FDG-PET), neuropsychiatric symptoms (evaluated using the NPI), and cognitive performance (measured by ADAS-Cog13 and MoCA) in individuals with AD, mild cognitive impairment (MCI), and cognitively normal (CN) participants. After adjusting for age, gender, education, and ApoE ɛ4 status, a significant positive relationship between CSF Aβ42 levels and cerebral glucose metabolism was observed in the MCI and AD groups, but not in the CN group. In the MCI group, higher cerebral glucose metabolism was associated with reductions in both neuropsychiatric and depressive symptoms, suggesting that higher glucose metabolism reflect higher activation state of investigated brain regions. In contrast, in the CN group, elevated CSF Aβ42 levels were directly linked to increased depressive symptoms, indicating that higher CSF Aβ42 may contribute to depression even in the absence of cognitive decline. Further analysis revealed that CSF Aβ42 levels were indirectly associated with reduced neuropsychiatric and depressive symptoms through enhanced cerebral glucose metabolism as mediator solely in the MCI group. Regarding cognitive performance, cerebral glucose metabolism showed a strong relationship with cognition in both the MCI and AD groups. Furthermore, higher CSF Aβ42 levels were positively associated with better cognitive performance in the MCI and AD groups, with cerebral glucose metabolism potentially mediating this relationship, while no effect was seen in the CN group. In short, CSF Aβ42 positively influenced cerebral glucose metabolism, which was linked to reduced neuropsychiatric and depressive symptoms as well as improved cognitive performance in MCI and AD groups.
The medial prefrontal cortex encodes procedural rules as sequential neuronal activity dynamics.
Ohno S, Nomoto M, Inokuchi K
Mol Brain · 2025 Jul · PMID 40597398 · Full text
The prefrontal cortex plays a crucial role in procedural rule learning; however, the specific neuronal mechanism through which it represents rules is unknown. We hypothesized that sequential neuronal activities in the pr...
The prefrontal cortex plays a crucial role in procedural rule learning; however, the specific neuronal mechanism through which it represents rules is unknown. We hypothesized that sequential neuronal activities in the prefrontal cortex encode these rules. To investigate this, we recorded neuronal activities in the medial prefrontal cortex of mice during rule learning using Ca imaging. We utilized a method based on convolutional negative matrix factorization, iSeq, to automatically detect temporal neuronal sequences in the recorded data. As rule learning advanced, these neuronal sequences began to encode critical information for rule execution. In mice that had mastered the rule, the dynamics of neuronal sequences could predict success and failure of reward acquisition. Furthermore, the composition of cell populations within the neuronal sequences was rearranged throughout the learning process. These findings suggest that as animals learn a rule, the medial prefrontal cortex continually updates its neuronal sequences to assign significance to behavioural actions crucial for reward acquisition.
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