Molecular Brain最新文献

Cytoskeletal remodeling drives morphological changes. Septin cytoskeleton assembles into hetero-oligomers. We previously demonstrated that late-phase long-term potentiation (L-LTP) induces smooth endoplasmic reticulum (sER) extension into dendritic spines via septin 3 (SEPT3), contributing to greater postsynaptic Ca²⁺ responses and enhanced activation of synaptically induced Ca²⁺ signaling. Sept3^-/- mice exhibit a reduced number of sER-containing spines and show impaired long-term spatial/object memory despite normal short-term memory. Additionally, SEPT3 binds the motor protein myosin-Va (MYO5A) upon elevated Ca²⁺ concentrations, facilitating sER extension from the dendritic shaft into the spine. MYO5A localizes on the sER membrane, while SEPT3 remains at the spine base, accumulating on sER upon electroconvulsive stimulation (ECS). However, the mechanism underlying SEPT3's delocalization from the spine base and its cooperative role with MYO5A in sER extension remains unclear. In this study, we demonstrate that SEPT3 is phosphorylated in a stimulation-dependent manner. Phosphorylation at Thr211 releases SEPT3 from the spine base, enabling sER extension with constitutively active MYO5A mutant (MYO5A-CCtr). These findings provide molecular insight into the role of SEPT3 phosphorylation in regulating sER dynamics that sustain long-term spine activation.

Fear generalization, which allows animals to respond adaptively to cues similar to original threatening ones, is generally beneficial for survival. However, an inability to distinguish between threat and safety, leading to the overgeneralization of fear to non-threatening stimuli, is maladaptive and is implicated in anxiety disorders such as post-traumatic stress disorder (PTSD). The neuropeptide gastrin-releasing peptide (GRP) is known to modulate fear memory under stress, yet its role in response to intense aversive stimuli remains less understood. In this study, we used GRP knockout (Grp^-/-) mice to examine the role of GRP in enhancing fear responses to conditioned stimulus (10 kHz tone, CS+) and non-conditioned stimulus (2 kHz tone, CS-) in a model of auditory fear conditioning with high-intensity footshocks following single acute restraint stress (RS). Our findings reveal that GRP is required not only for enhanced response to CS+ but also for generalized fear responses to CS-. Furthermore, we observed that infusion of GRP into the auditory cortex (AC) of Grp^-/- mice restores freezing behavior in response to CS- and fear generalization. Additionally, GRP in the AC is essential for the generalization of CS+ responsive neurons to respond to CS- during fear memory retrieval. These results highlight a novel role for GRP in the mechanisms underlying maladaptive fear in highly stressful situations, offering potential new targets for treating anxiety-related disorders.

Exercise evokes many physiological changes, including the release of hormones and growth factors that are known to improve cognition via unknown mechanisms. Here, we have compared the ability of two physiologically relevant factors, corticosterone (CORT) and brain-derived neurotrophic factor (BDNF), to affect long-term potentiation (LTP) in the hippocampus. Using a compressed theta-burst stimulation (cTBS) protocol, we found that CORT has no effect on LTP, BDNF enhances LTP and combined CORT + BDNF treatment results in significantly greater LTP. We also find that CORT + BDNF, but not either compound alone, results in phosphorylation of protein kinase A (PKA). These findings show that BDNF and CORT act synergistically to enhance LTP at these synapses, potentially via a PKA-dependent mechanism. Such a synergistic action could underlie the positive cognitive effects of exercise.

Kv1.3 channels in microglia are pivotal in regulating neuroinflammation. The antipsychotic chlorpromazine (CPZ) demonstrates anti-inflammatory effects by decreasing Kv1.3 activity in mPFC microglia. However, the precise mechanism of CPZ's effect in the mPFC remains unclear, given that CPZ is known to inhibit dopamine receptors and the mPFC contains various cell types with dopamine receptors. In this study, we investigate how CPZ inhibits Kv1.3 channels using human Kv1.3 channel-expressing Xenopus laevis oocytes. CPZ directly inhibits Kv1.3 channel currents in a concentration-dependent manner. The CPZ-mediated Kv1.3 channel inhibition is not voltage-dependent, and CPZ accelerates Kv1.3 channel inactivation without significantly affecting its activation. Our findings suggest that CPZ directly blocks Kv1.3 channels without involving other ion channels or receptors, including dopamine receptors, thereby contributing to the understanding of its neuroinflammation-suppressing mechanism.

Hypoxic-ischemic brain damage (HIBD) is a significant cause of neonatal death and neurological dysfunction. Following this injury, activated microglia can lead to a series of inflammatory responses. Gastrodin (GAS), a polyphenol extracted from the Chinese herbal medicine Gastrodia elata Blume, has demonstrated antioxidant and anti-inflammatory effects. This study investigated the neuroprotective impact of GAS in HIBD mice model and in BV2 cells subjected to oxygen-glucose deprivation (OGD) treatment. Expression of various members of the Ccr2/Akt/Gsk-3β, including Ccl2, Ccr2, Akt, p-Akt, Gsk-3β, p-Gsk-3β and inflammatory factors TNF-α and IL-1β in activated microglia was assessed by Western blotting, immunofluorescence, and qRT-PCR in HIBD in postnatal mice, and in OGD-induced BV2 microglia in vitro with or without GAS treatment. The present results showed that GAS effectively reduces the expression of Ccl2 and Ccr2, increases the phosphorylation levels of Akt and Gsk-3β, and decreases the expression of the TNF-α and IL-1β. Additionally, we have shown that inhibition of Ccr2 by RS102895 increased the expression of p-Akt and p-Gsk-3β, and attenuate production of proinflammatory mediators in activated microglia. Of note, the expression of p-Akt, p-Gsk-3β, TNF-α and IL-1β remained unchanged after the combination of gastrodin and RS102895. Taken together, we conclude that GAS can play a protective role in reducing the neuroinflammatory response after HIBD. It is suggested that this is mainly through up-regulating the Akt/Gsk-3β signaling pathway via the Ccr2 receptor in the present experimental paradigm.

Astrocytes are critical in regulating synaptic transmission in the central nervous system (CNS). The spinal dorsal horn (SDH) is a crucial region that processes and integrates somatosensory information from the periphery and transmits it to the brain. Our previous work demonstrated that stimulation of an astrocyte population in the SDH, characterized by the expression of hairy and enhancer of split 5 (Hes5), causes pain hypersensitivity. However, the mechanism by which Hes5⁺ astrocytes modulate synaptic transmission in the SDH remains unclear. In this study, using electrophysiological and cell type-specific functional manipulation approaches, we found that chemogenetic stimulation of Hes5⁺ SDH astrocytes enhanced Aδ and C fiber-mediated excitatory postsynaptic currents in lamina I neurons. A pharmacological blockade of the glycine binding site of N-methyl-D-aspartate (NMDA) receptors prevented the astrocytic enhancement. These findings suggest that Hes5⁺ astrocytes in the SDH enhance synaptic transmission from primary afferent nociceptors to lamina I neurons by potentiating NMDA receptor activity.

Associated to glutamatergic neurotransmission, Neuroligin-1 (NLGN1) is a synaptic adhesion molecule with roles in the regulation of behavioral states and cognitive function. It was shown to shape electrocorticographic (ECoG) activity during wakefulness and sleep in male mice, including aperiodic activity under baseline conditions. Given that the expression of Neuroligins (Nlgn) differs between sexes, we here aim to characterize the impact of the absence of NLGN1 on the wakefulness and sleep architecture, rhythmic and arrhythmic activity dynamics, and responses to sleep deprivation in female animals. Nlgn1 knockout (KO) female mice and wild-type (WT) female littermates were implanted with ECoG electrodes, and ECoG signals were recorded for 48 hours comprising a 24-hour baseline, followed by a 6-hour sleep deprivation and 18 hours of undisturbed recovery (REC). Time spent in wakefulness, slow wave sleep (SWS) and paradoxical sleep (PS), and their alternation were interrogated, and ECoG activities were quantified using a standard spectral analysis and a multifractal analysis. Nlgn1 KO females spent more time in PS during the light period under baseline in comparison to WT females. This difference was observed along with more PS bouts and a shorter overall PS bout duration, indicative of a fragmented PS. Additionally, Nlgn1 KO females displayed less ECoG power between 8 and 13 Hz during wake, less power between 1.25 and 3.5 Hz during PS, and more between 2.5 and 3.75 Hz during SWS in comparison to WT. Under both baseline and REC, NLGN1 absence in females was significantly associated with a higher value of the most prevalent Hurst exponent (Hm) during SWS, which points to a higher persistence across scales of ECoG aperiodic activity. Indications for alterations in the daily dynamics of the Dispersion of Hurst exponents around Hm were also found during SWS in KO females. The present study highlights differences in wake/sleep architecture, and in periodic (rhythmic) and aperiodic (arrhythmic/multifractal) activities in female mice lacking NLGN1. These findings provide additional support to a role for NLGN1 in shaping the ECoG organization, in particular during sleep, and will help understanding the origin of sleep disturbances in neuropsychiatric diseases.

Neurofibrillary tangles (NFTs), composed of tau protein fibrils, together with brain inflammation and synaptic loss, are neuropathological hallmarks of several neurodegenerative diseases, including Alzheimer's disease. Compared with tau fibrils, more water-soluble assemblies of either recombinant or patient-derived tau have been reported to exert relatively potent rapid synaptotoxic effects, including inhibition of synaptic long-term potentiation (LTP) in the hippocampus. Less is known regarding the action of exogenous tau soluble assemblies on the opposite form of synaptic plasticity, long-term depression (LTD). We compared the synaptic plasticity actions of two relatively standard preparations of soluble recombinant tau assemblies, (i) fibril-derived soluble sonicated tau aggregates (SτAs) and (ii) oligomer-enriched tau (oTau) prepared from monomers. Consistent with previous findings, intracerebroventricular injections of either SτAs or oTau acutely inhibited high-frequency stimulation-induced LTP at CA3-to-CA1 synapses in the anaesthetized rat hippocampus. However, LTP inhibition by oTau, but not SτAs, was prevented by co-injection with the conformational anti-tau monoclonal antibody, TOMA1. Furthermore, in contrast to SτAs, which inhibited LTD, injection of oTau potently facilitated LTD, decreasing the threshold for LTD induction by low-frequency stimulation. To test the role of pro-inflammatory cytokines in mediating the disruptive effects of the two forms of soluble tau on synaptic plasticity we pre-injected etanercept, a decoy receptor for tumor necrosis factor alpha (TNFα). Etanercept reduced the disruption of synaptic plasticity by oTau but not by SτAs. Moreover, injection of exogenous TNFα mimicked the facilitation of LTD by oTau, consistent with a role of this pro-inflammatory cytokine in LTD facilitation.These data provide evidence that preparations of soluble tau containing either monomer- or fibril-derived assemblies disrupt LTP and LTD via different mechanisms. Intriguingly, when oTau and SτAs were applied together, LTD block predominated. Thus, if similar synaptotoxic soluble tau assemblies are present together later during the disease process, as seems likely, inhibition of synaptic weakening processes is predicted to predominate. Equally, reducing TNFα would be expected to be more effective when the monomer-derived soluble tau assemblies are the dominant synaptotoxic species. We conclude that oTau and SτAs provide useful means to explore ways of targeting different synaptotoxic soluble tau species in tauopathies.

Pericytes in the central nervous system are essential for maintaining blood-brain barrier function, regulating blood flow, modulating immune responses, and interacting closely with surrounding cells of the neurovascular unit to support brain homeostasis. Increasing evidence has highlighted their involvement in age-related neuroinflammation, where their dysfunction may contribute to sustained inflammatory states associated with neurodegenerative disorders. Here, we compared inflammatory responses to lipopolysaccharide (LPS) in primary cerebral pericytes from neonatal and adult mice and adult humans. Our findings indicate that neonatal mouse pericytes display heightened inflammatory activation, with elevated levels of ICAM-1 and several cytokines, compared to adult mouse pericytes reflecting a more reactive phenotype. In contrast, adult mouse pericytes exhibited a significantly reduced cytokine release profile, suggesting lower responsiveness. Notably, while cytokine secretion patterns in adult human pericytes, in part, mirrored those in neonatal mouse pericytes, nitric oxide production, which was observed in mouse pericytes, was absent in the human cells. These results underscore species- and age-dependent variations in cellular behavior, emphasizing the importance of utilizing human brain cell systems when conducting research on neuroinflammation. Understanding these distinctions is vital for designing accurate studies and developing targeted therapies for neuroinflammatory conditions.

Limited spontaneous recovery occurs after spinal cord injury (SCI). However, current knowledge indicates that multiple forms of axon growth in spared axons can lead to circuit reorganization. Intravenous infusion of mesenchymal stem cells (MSCs) provides functional improvements after SCI with an increased axonal network. In this study, we examined how intravenous infusion of MSCs facilitates axonal connections in the rubrospinal tract (RST), one of the significant descending tracts, using AAV neuronal tracing techniques. Our finding demonstrated that infused MSCs significantly enhanced axonal signal intensity in the RST, not only around the injury site but also in the rostral and caudal regions, suggesting that neural circuit reorganization is facilitated.