bioRxiv Subject Collection: Neuroscience's Journal
[Most Recent Entries]
[Calendar View]
Sunday, January 19th, 2025
| Time |
Event |
| 1:03a |
Cholinergic Modulation of Chandelier Cells via Heteromeric Nicotinic Receptors in Prefrontal Cortex
Chandelier cells (ChCs) are a distinct subtype of GABAergic interneurons that form vertical arrays of presynaptic boutons targeting the axon initial segment (AIS) of pyramidal neurons (PNs). They are particularly abundant in prefrontal cortex, where cholinergic inputs modulate cognitive functions and shape ChC axonal development. However, the effects of the cholinergic system on ChC activity in the adult brain remain largely unexplored. Here, using a genetic intersectional strategy (VipR2-Pvalb-Ai65) in adult mice, we selectively labeled ChCs in the secondary motor cortex (M2). Immunohistochemistry and electrophysiology confirmed morphological and functional properties distinguishing them from basket cells. We found that these ChCs exhibit an inward current in response to nicotinic acetylcholine receptor (nAChR) agonists. Pharmacological blockade and fluorescent in situ hybridization revealed that this effect is primarily mediated by heteromeric nAChRs containing {beta}2 subunits, with a smaller contribution from 3 subunits. Optogenetic stimulation of basal forebrain (BF) cholinergic axons evoked inward currents in ChCs, confirming a functional cholinergic drive. Furthermore, in vivo two-photon calcium imaging revealed a strong correlation between ChC activity and behavioral markers of arousal, including locomotion and pupil dilation. Importantly, the application of nicotinic receptor antagonists significantly diminished ChC activity during movement. Together, these results indicate that ChCs are modulated by cholinergic input via heteromeric nAChRs, emphasizing their importance in facilitating state-dependent cortical dynamics. | | 3:46a |
Post-movement beta rebound reflects strategic re-aiming during motor adaptation, but not re-aiming accuracy
Motor adaptation results from several interacting learning mechanisms, including learning via cognitive strategies and implicit adaptation. While strategy-based and implicit learning can be dissociated at a behavioural level, their underlying systems-level physiology is poorly understood. A neural signal that undergoes pronounced changes during motor adaptation is the post-movement beta-rebound (PMBR). However, it is unclear how these changes relate to the specific learning mechanisms that contribute to motor adaptation. We measured electroencephalography (EEG) while healthy participants (N=27) performed reaching movements towards a target. In most trials, a cursor showed the veridical position of the unseen hand, however, for some reaches, the direction of the cursor was rotated relative to the position of the hand. Participants were informed that, once a rotation occurred, it could persist for a single trial (1x condition), or for two consecutive trial (2x condition). In the 2x condition, participants could therefore redirect the rotated cursor through the target in the second rotated trial by re-aiming, while they had to continue aiming at the target in the 1x condition. We observed a stronger decrease of PMBR following the first rotated reach in the 2x condition, compared to the 1x condition, despite similar kinematics. This corroborates our previous results that PMBR reflects strategic re-aiming (Korka et al., 2023). However, when we collapsed data from the two studies (total N=53), we found that the degree to which the PMBR decreases does not predict re-aiming accuracy. We discuss the role of PMBR in motor adaptation, including implications for clinical disorders. | | 3:46a |
Efficacy of functional connectome fingerprinting using tangent-space brain networks
Functional connectomes (FCs) are estimations of brain region interaction derived from brain activity, often obtained from functional Magnetic Resonance Imaging recordings. Quantifying the distance between FCs is important for understanding the relation between behaviour, disorders, disease, and changes in connectivity. Recently, tangent space projections, which account for the curvature of the mathematical space of FCs, have been proposed for calculating FC distances. We compare the efficacy of this approach relative to the traditional method in the context of subject identification using the Midnight Scan Club dataset, in order to study resting-state and task-based subject discriminability. The tangent space method is found to universally out-perform the traditional method. We also focus on the subject identification efficacy of subnetworks. Certain subnetworks are found to outperform others, a dichotomy which largely follows the `control' and `processing' categorization of resting state networks, and relates subnetwork flexibility with subject discriminability. Identification efficacy is also modulated by tasks, though certain subnetworks appear task independent. The uniquely long recordings of the dataset also allow for explorations of resource requirements for effective subject identification. The tangent space method is found to universally require less data, making it well suited when only short recordings are available. | | 3:46a |
Impact of meningioma and glioma on whole-brain dynamics
Brain tumors, particularly meningiomas and gliomas, can profoundly affect neural function, yet their impact on brain dynamics remains incompletely understood. This study investigates alterations in normal brain function among meningioma and glioma patients by assessing dynamical complexity through the Intrinsic Ignition Framework. We analyzed resting-state fMRI data from 34 participants to quantify brain dynamics using intrinsic ignition and metastability metrics. Our results revealed distinct patterns of disruption: glioma patients showed significant reductions in both metrics compared to controls, indicating widespread network disturbances. In contrast, meningioma patients exhibited significant changes predominantly in regions with substantial tumor involvement. Resting-state network analysis demonstrated strong metastability and metastability/ignition correlations between regions in controls, which were slightly weakened in meningioma patients and severely disrupted in glioma patients. These findings highlight the differential impacts of gliomas and meningiomas on brain function, offering insights into their distinct pathophysiological mechanisms. Furthermore, these results show that brain dynamics metrics can be effective biomarkers for identifying disruptions in brain information transmission caused by tumors. | | 3:46a |
Microglial SIRT2 deficiency aggravates cognitive decline and amyloid pathology in Alzheimer's disease
Sirtuin 2 (SIRT2), a NAD+-dependent deacetylase, has been implicated in aging and neurodegenerative diseases such as Alzheimer's disease (AD). While global SIRT2 inhibition has shown promise in reducing amyloid-beta pathology and cognitive deficits in different mouse models of AD, peripheral SIRT2 inhibition has been associated with adverse effects, such as increased inflammation. This suggests that targeted inhibition of specific cellular populations within the brain may represent a more precise and effective approach for the treatment of AD. To explore this hypothesis, we generated a conditional microglial SIRT2 knockout mouse model in the context of AD. Our results reveal that microglial SIRT2 reduction does not confer protective effects in the APP/PS1 model; rather, it aggravates cognitive decline, accelerates amyloid plaque deposition, and increases levels of pro-inflammatory cytokines at early stages of AD pathology. Transcriptomic analysis further indicates that SIRT2-deficient microglia exhibit altered expression of genes associated with aging and synaptic dysfunction. This phenotype was accompanied by increased phagocytosis of synaptic elements and impaired long-term potentiation. These findings suggest that while SIRT2 inhibition in some contexts may be beneficial, targeted inhibition within microglia could accelerate AD progression, underscoring the need for cell-specific approaches when considering SIRT2 as a therapeutic target. | | 3:46a |
Rescue of hippocampal synaptic plasticity and memory performance by Fingolimod (FTY720) in APP/PS1 model of Alzheimer's disease is accompanied by correction in metabolism of sphingolipids, polyamines, and phospholipid saturation composition
Previously, our metabolomic, transcriptomic, and genomic studies characterized the ceramide/sphingomyelin pathway as a therapeutic target in Alzheimers disease, and we demonstrated that FTY720, a sphingosine-1-phospahate receptor modulator approved for treatment of multiple sclerosis, recovers synaptic plasticity and memory in APP/PS1 mice. To further investigate how FTY720 rescues the pathology, we performed metabolomic analysis in brain, plasma, and liver of trained APP/PS1 and wild-type mice. APP/PS1 mice showed area-specific brain disturbances in polyamines, phospholipids, and sphingolipids. Most changes were completely or partially normalized in FTY720-treated subjects, indicating rebalancing the "sphingolipid rheostat", reactivating phosphatidylethanolamine synthesis via mitochondrial phosphatidylserine decarboxylase pathway, and normalizing polyamine levels that support mitochondrial activity. Synaptic plasticity and memory were rescued, with spermidine synthesis in temporal cortex best corresponding to hippocampal CA3-CA1 plasticity normalization. FTY720 effects, also reflected in other pathways, are consistent with promotion of mitochondrial function, synaptic plasticity, and anti-inflammatory environment, while reducing pro-apoptotic and pro-inflammatory signals. | | 5:42a |
Lecanemab binds to transgenic mouse model-derived amyloid-β fibril structures resembling Alzheimer 's disease type-I, type-II and Arctic folds
Lecanemab, an Alzheimers disease US Food and Drug Administration approved monoclonal antibody was previously reported to have a high affinity against intermediately sized amyloid-{beta} aggregates. Subsequently, it was observed by immunogold labelling that lecanemab can also bind to human type-I amyloid-{beta} fibrils. Therefore, to determine whether lecanemab binds to amyloid-{beta} fibril structures other than type-I, we performed immunogold labelling on extracted amyloid-{beta} fibril preparations from six different Alzheimers disease mouse models whose structures were previously solved by cryo-EM. Our results show that lecanemab exhibits high binding affinity to amyloid-{beta} fibril structures that have a flexible N-terminus in common, as it is the case for type-I, type-II and murine type-III amyloid-{beta} fibril polymorphs which resemble or are identical to human structures observed in sporadic and familial cases of Alzheimers disease, including a case with the Arctic (E22G) mutation. In contrast, only weak, if any, lecanemab binding was observed for amyloid-{beta} fibril folds with a fixed and ordered N-terminus.
Key points- Lecanemab binds to A{beta} fibrils from several Alzheimers disease tg-mice whose structures resemble the type-I, type-II and Arctic folds found in Alzheimers patients, all of which share a flexible, unstructured N-terminus.
- Lecanemab is therefore expected to be active against all common familial and sporadic Alzheimers cases containing these folds.
- Lecanemab binding ability is unaffected by and tolerates the Arctic E22G mutation, at least in type-I or Arctic folds.
- Weak, if any, lecanemab binding was observed to A{beta} fibrils derived from tg-SwDI mice, whose structures DI1, DI2 and DI3 all share structured and fixed N-termini.
- Since the fixed N-termini of tg-SwDI DI1 fibrils and human meningeal A{beta}40 fibrils derived from CAA-affected brain are identical, most likely preventing lecanemab binding, treatment with lecanemab may be less or ineffective against CAA, but may explain the reported beneficial low ARIA-E frequency with this antibody.
Table of Contents Graphic (TOC)
O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=119 SRC="FIGDIR/small/633637v1_ufig1.gif" ALT="Figure 1">
View larger version (27K):
org.highwire.dtl.DTLVardef@dacc05org.highwire.dtl.DTLVardef@88809aorg.highwire.dtl.DTLVardef@1b322a3org.highwire.dtl.DTLVardef@1a711be_HPS_FORMAT_FIGEXP M_FIG C_FIG | | 5:42a |
Lipid-protecting disulfide bridges are the missing molecular link between ApoE4 and sporadic Alzheimers disease in humans
As the principal lipid transporter in the human brain, apolipoprotein E (ApoE) is tasked with the transport and protection of highly vulnerable lipids required to support and remodel neuronal membranes, in a process that is dependent on ApoE receptors. Human APOE allele variants that encode proteins differing only in the number of cysteine (Cys)-to-arginine (Arg) exchanges (ApoE2 [2 Cys], ApoE3 [1 Cys], ApoE4 [0 Cys]) comprise the strongest genetic risk factor for sporadic Alzheimers disease (AD); however, the specific molecular feature(s) and resultant mechanisms that underlie these isoform-dependent effects are unknown. One signature feature of Cys is the capacity to form disulfide (Cys-Cys) bridges, which are required to form disulfide bridge-linked dimers and multimers. Here we propose the overarching hypothesis that the super-ability (for ApoE2), intermediate ability (for ApoE3) or inability (for ApoE4) to form lipid-protecting intermolecular disulfide bridges, is the central molecular determinant accounting for the disparate effects of APOE alleles on AD risk and amyloid-{beta} and Tau pathologies in humans. We posit that presence and abundance of Cys in human ApoE3 and ApoE2 respectively, conceal and protect vulnerable lipids transported by ApoE from peroxidation by enabling formation of ApoE homo-dimers/multimers and heteromeric ApoE complexes such as ApoE-ApoJ and ApoE-ApoD. We thus propose that the inability to form intermolecular disulfide bridges makes ApoE4-containing lipoproteins uniquely vulnerable to peroxidation and its downstream consequences. Consistent with our model, we found that brain-enriched polyunsaturated fatty acid-containing phospholipids induce disulfide-dependent dimerization and multimerization of ApoE3 and ApoE2 (but not ApoE4). By contrast, incubation with the peroxidation-resistant lipid DMPC or cholesterol alone had minimal effects on dimerization. These novel concepts and findings are integrated into our unifying model implicating peroxidation of ApoE-containing lipoproteins, with consequent ApoE receptor-ligand disruption, as the initiating molecular events that ultimately lead to AD in humans.
HighlightsO_LIAPOE alleles are the strongest genetic risk factor for sporadic Alzheimers disease (AD)
C_LIO_LIAPOE alleles encode proteins that differ only in the number of Cys{longrightarrow}Arg exchanges
C_LIO_LIDespite 30 years of inquiry, mechanisms linking Cys{longrightarrow}Arg exchanges to AD remain unknown
C_LIO_LIPUFA-phospholipids induced disulfide bridge formation in ApoE3 and ApoE2 (but not ApoE4)
C_LIO_LIWe hypothesize that disulfide bridges in ApoE protect vulnerable lipids from peroxidation
C_LIO_LIWe propose that lipid-protecting disulfide bridges explain APOE allele-dependent AD risks
C_LI | | 8:17a |
Biased replay of aversive and uncertain outcomes underlies irrational decision making
Humans often make irrational decisions when facing uncertain or aversive future events despite careful deliberation. How we make choices, including irrational ones1,2, has been the object of extensive study both behaviourally and neurally3-6 and is the focus of influential behavioural economic theories7-9. Yet, little is known about how these (irrational) decisions are carved out in the brain. Here, using magnetoencephalography (MEG), we show that the construction and outcome evaluation of irrational decisions involves rapid, sequential state reactivation, or "replay."10. During deliberation, we show that forward replay is biased towards choice options with more negative and uncertain outcomes, with this bias further amplified immediately preceding irrational choice. Likewise, post-decision evaluation relates to replay in a choice-dependent manner. Following irrational choices, relief-like signals were evident as stronger backward replay of worse counterfactual options, while after rational decisions, regret-like signals appeared as stronger backward replay of better counterfactual options. Together, these findings suggest that neural replay shapes both the formation and reflection of irrational decisions, and poise replay as a candidate mechanism underlying pervasive decision biases in humans. |
|