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Progress in Neuro-psychopharmacology &... Jun 2024Anorexia nervosa (AN) is characterized by hyperactivation of the hypothalamic-pituitary-adrenal axis and cognitive deficits. However, little is known about the rapid...
OBJECTIVE
Anorexia nervosa (AN) is characterized by hyperactivation of the hypothalamic-pituitary-adrenal axis and cognitive deficits. However, little is known about the rapid non-genomic stress response involvement. This study investigates the molecular, structural and behavioral signatures of the anorexic phenotype induction in female rats on stress-related mechanisms in the hippocampus.
METHOD
Female adolescent rats, exposed to the combination of food restriction and wheel access, i.e., the activity-based anorexia (ABA) protocol, were sacrificed in the acute phase of the pathology (postnatal day [P]42) or following a 7-day recovery period (P49).
RESULTS
ABA rats, in addition to body weight loss and increased wheel activity, alter their pattern of activity over days, showing increased food anticipatory activity, a readout of their motivation to engage in intense physical activity. Corticosterone plasma levels were enhanced at P42 while reduced at P49 in ABA rats. In the membrane fraction of the hippocampus, we found reduced glucocorticoid receptor levels together with reduced expression of caldesmon, n-cadherin and neuroligin-1, molecular markers of cytoskeletal stability and glutamatergic homeostasis. Accordingly, structural analyses revealed reduced dendritic spine density, a reduced number of mushroom-shaped spines, together with an increased number of thin-shaped spines. These events are paralleled by impairment in spatial memory measured in the spatial order object recognition test. These effects persisted even when body weight of ABA rats was restored.
DISCUSSION
Our findings indicate that ABA induction orchestrates hippocampal maladaptive structural and functional plasticity, contributing to cognitive deficits, providing a putative mechanism that could be targeted in AN patients.
PubMed: 38901757
DOI: 10.1016/j.pnpbp.2024.111065 -
Journal of Neurochemistry Jun 2024Kelch-like family member 17 (KLHL17), an actin-associated adaptor protein, is linked to neurological disorders, including infantile spasms and autism spectrum disorders....
Kelch-like family member 17 (KLHL17), an actin-associated adaptor protein, is linked to neurological disorders, including infantile spasms and autism spectrum disorders. The key morphological feature of Klhl17-deficient neurons is impaired dendritic spine enlargement, resulting in the amplitude of calcium events being increased. Our previous studies have indicated an involvement of F-actin and the spine apparatus in KLHL17-mediated dendritic spine enlargement. Here, we show that KLHL17 further employs different mechanisms to control the expression of two types of glutamate receptors, that is, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and kainate receptors (KARs), to regulate dendritic spine enlargement and calcium influx. We deployed proteomics to reveal that KLHL17 interacts with N-ethylmaleimide-sensitive fusion protein (NSF) in neurons, with this interaction of KLHL17 and NSF enhancing NSF protein levels. Consistent with the function of NSF in regulating the surface expression of AMPAR, Klhl17 deficiency limits the surface expression of AMPAR, but not its total protein levels. The NSF pathway also contributes to synaptic F-actin distribution and the dendritic spine enlargement mediated by KLHL17. KLHL17 is known to act as an adaptor mediating degradation of the KAR subunit GluK2 by the CUL3 ubiquitin ligase complex, and Klhl17 deficiency impairs activity-dependent degradation of GluK2. Herein, we further demonstrate that GluK2 is critical to the increased amplitude of calcium influx in Klhl17-deficient neurons. Moreover, GluK2 is also involved in KLHL17-regulated dendritic spine enlargement. Thus, our study reveals that KLHL17 controls AMPAR and KAR expression via at least two mechanisms, consequently regulating dendritic spine enlargement. The regulatory effects of KLHL17 on these two glutamate receptors likely contribute to neuronal features in patients suffering from certain neurological disorders.
PubMed: 38898681
DOI: 10.1111/jnc.16148 -
Nature Methods Jun 2024Volumetric imaging of synaptic transmission in vivo requires high spatial and high temporal resolution. Shaping the wavefront of two-photon fluorescence excitation...
Volumetric imaging of synaptic transmission in vivo requires high spatial and high temporal resolution. Shaping the wavefront of two-photon fluorescence excitation light, we developed Bessel-droplet foci for high-contrast and high-resolution volumetric imaging of synapses. Applying our method to imaging glutamate release, we demonstrated high-throughput mapping of excitatory inputs at >1,000 synapses per volume and >500 dendritic spines per neuron in vivo and unveiled previously unseen features of functional synaptic organization in the mouse primary visual cortex.
PubMed: 38898094
DOI: 10.1038/s41592-024-02309-3 -
European Journal of Pharmacology Aug 2024Repeated exposure to propofol during early brain development is associated with anxiety disorders in adulthood, yet the mechanisms underlying propofol-induced...
Repeated exposure to propofol during early brain development is associated with anxiety disorders in adulthood, yet the mechanisms underlying propofol-induced susceptibility to anxiety disorders remain elusive. The lateral septum (LS), primarily composed of γ-aminobutyric acidergic (GABAergic) neurons, serves as a key brain region in the regulation of anxiety. However, it remains unclear whether LS GABAergic neurons are implicated in propofol-induced anxiety. Therefore, we conducted c-Fos immunostaining of whole-brain slices from mice exposed to propofol during early life. Our findings indicate that propofol exposure activates GABAergic neurons in the LS. Selective activation of LS GABAergic neurons resulted in increased anxiety-like behavior, while selective inhibition of these neurons reduced such behaviors. These results suggest that the LS is a critical brain region involved in propofol-induced anxiety. Furthermore, we investigated the molecular mechanism of propofol-induced anxiety in the LS. Microglia activation underlies the development of anxiety. Immunofluorescence staining and Western blot analysis of LS revealed activated microglia and significantly elevated levels of phospho-NF-κB p65 protein. Additionally, a decrease in the number of neuronal spines was observed. Our study highlights the crucial role of the LS in the development of anxiety-like behavior in adulthood following childhood propofol exposure, accompanied by the activation of inflammatory pathways.
Topics: Propofol; Animals; Anxiety; Mice; Male; GABAergic Neurons; Behavior, Animal; Microglia; Proto-Oncogene Proteins c-fos; Mice, Inbred C57BL; Transcription Factor RelA; Dendritic Spines
PubMed: 38897021
DOI: 10.1016/j.ejphar.2024.176756 -
BioRxiv : the Preprint Server For... Jun 2024Accurate and unbiased reconstructions of neuronal morphology, including quantification of dendritic spine morphology and distribution, are widely used in neuroscience...
Accurate and unbiased reconstructions of neuronal morphology, including quantification of dendritic spine morphology and distribution, are widely used in neuroscience but remain a major roadblock for large-scale analysis. Traditionally, spine analysis has required labor-intensive manual annotation, which is prone to human error and impractical for large 3D datasets. Previous automated tools for reconstructing neuronal morphology and quantitative dendritic spine analysis face challenges in generating accurate results and, following close inspection, often require extensive manual correction. While recent tools leveraging deep learning approaches have substantially increased accuracy, they lack functionality and useful outputs, necessitating additional tools to perform a complete analysis and limiting their utility. In this paper, we describe Restoration Enhanced SPine And Neuron (RESPAN) analysis, a new comprehensive pipeline developed as an open-source, easily deployable solution that harnesses recent advances in deep learning and GPU processing. Our approach demonstrates high accuracy and robustness, validated extensively across a range of imaging modalities for automated dendrite and spine mapping. It also offers extensive visual and tabulated data outputs, including detailed morphological and spatial metrics, dendritic spine classification, and 3D renderings. Additionally, RESPAN includes tools for validating results, ensuring scientific rigor and reproducibility.
PubMed: 38895232
DOI: 10.1101/2024.06.06.597812 -
BioRxiv : the Preprint Server For... Jun 2024Angelman syndrome (AS) is a rare genetic neurodevelopmental disorder with profoundly debilitating symptoms with no FDA-approved cure or therapeutic. Brain-derived...
Angelman syndrome (AS) is a rare genetic neurodevelopmental disorder with profoundly debilitating symptoms with no FDA-approved cure or therapeutic. Brain-derived neurotrophic factor (BDNF), and its receptor TrkB, have a well-established role as regulators of synaptic plasticity, dendritic outgrowth, dendritic spine formation and maintenance. Previously, we reported that the association of PSD-95 with TrkB is critical for intact BDNF signaling in the AS mouse model, as illustrated by attenuated PLCγ and PI3K signaling and intact MAPK pathway signaling. These data suggest that drugs tailored to enhance the TrkB-PSD-95 interaction may provide a novel approach for the treatment of AS and a variety of NDDs. To evaluate this critical interaction, we synthesized a class of high-affinity PSD-95 ligands that bind specifically to the PDZ3 domain of PSD-95, denoted as Syn3 peptidomimetic ligands. We evaluated Syn3 and its analog D-Syn3 (engineered using dextrorotary (D)-amino acids) using the exon 2 deletion mouse model of AS. Following systemic administration of Syn3 and D-Syn3, we demonstrated improvement in the seizure domain of AS. Learning and memory using the novel object recognition assay also illustrated improved cognition following Syn3 and D-Syn3, along with restored long-term potentiation. Finally, D-Syn3 treated mice showed a partial rescue in motor learning. Neither Syn3 nor D-Syn3 improved gross exploratory locomotion deficits, nor gait impairments that have been well documented in the AS rodent models. These findings highlight the need for further investigation of this compound class as a potential therapeutic for AS and other genetic NDDs.
PubMed: 38895218
DOI: 10.1101/2024.06.07.597833 -
Cells Jun 2024Methyl-CpG-binding protein 2 () is an epigenetic modulator and numerous studies have explored its impact on the central nervous system manifestations. However, little...
Methyl-CpG-binding protein 2 () is an epigenetic modulator and numerous studies have explored its impact on the central nervous system manifestations. However, little attention has been given to its potential contributions to the peripheral nervous system (PNS). To investigate the regulation of in the PNS on specific central regions, we generated mice with the sensory-neuron-specific deletion of the gene and found the mutant mice had a heightened sensitivity to temperature, which, however, did not affect the sense of motion, social behaviors, and anxiety-like behavior. Notably, in comparison to mice, mice exhibited improved learning and memory abilities. The levels of hippocampal synaptophysin and PSD95 proteins were higher in mice than in mice. Golgi staining revealed a significant increase in total spine density, and dendritic arborization in the hippocampal pyramidal neurons of mice compared to mice. In addition, the activation of the BDNF-TrkB-CREB1 pathway was observed in the hippocampus and spinal cord of mice. Intriguingly, the hippocampal BDNF/CREB1 signaling pathway in mutant mice was initiated within 5 days after birth. Our findings suggest a potential therapeutic strategy targeting the BDNF-TrkB-CREB1 signaling pathway and peripheral somasensory neurons to treat learning and cognitive deficits associated with Mecp2 disorders.
Topics: Animals; Methyl-CpG-Binding Protein 2; Hippocampus; Dendritic Spines; Mice; Cognition; Brain-Derived Neurotrophic Factor; Sensory Receptor Cells; Cyclic AMP Response Element-Binding Protein; Male; Signal Transduction; Mice, Inbred C57BL; Receptor, trkB
PubMed: 38891120
DOI: 10.3390/cells13110988 -
Neural Regeneration Research Mar 2025Tropomyosin receptor kinase B (TrkB) signaling plays a pivotal role in dendritic growth and dendritic spine formation to promote learning and memory. The...
Tropomyosin receptor kinase B (TrkB) signaling plays a pivotal role in dendritic growth and dendritic spine formation to promote learning and memory. The activity-dependent release of brain-derived neurotrophic factor at synapses binds to pre- or postsynaptic TrkB resulting in the strengthening of synapses, reflected by long-term potentiation. Postsynaptically, the association of postsynaptic density protein-95 with TrkB enhances phospholipase Cγ-Ca2+/calmodulin-dependent protein kinase II and phosphatidylinositol 3-kinase-mechanistic target of rapamycin signaling required for long-term potentiation. In this review, we discuss TrkB-postsynaptic density protein-95 coupling as a promising strategy to magnify brain-derived neurotrophic factor signaling towards the development of novel therapeutics for specific neurological disorders. A reduction of TrkB signaling has been observed in neurodegenerative disorders, such as Alzheimer's disease and Huntington's disease, and enhancement of postsynaptic density protein-95 association with TrkB signaling could mitigate the observed deficiency of neuronal connectivity in schizophrenia and depression. Treatment with brain-derived neurotrophic factor is problematic, due to poor pharmacokinetics, low brain penetration, and side effects resulting from activation of the p75 neurotrophin receptor or the truncated TrkB.T1 isoform. Although TrkB agonists and antibodies that activate TrkB are being intensively investigated, they cannot distinguish the multiple human TrkB splicing isoforms or cell type-specific functions. Targeting TrkB-postsynaptic density protein-95 coupling provides an alternative approach to specifically boost TrkB signaling at localized synaptic sites versus global stimulation that risks many adverse side effects.
PubMed: 38886937
DOI: 10.4103/NRR.NRR-D-23-02000 -
The Journal of Neuroscience : the... Jun 2024The small G-protein Rac1 promotes the formation of filamentous actin (F-Actin). Actin is a major component of dendritic spines, and we previously found that alcohol...
The small G-protein Rac1 promotes the formation of filamentous actin (F-Actin). Actin is a major component of dendritic spines, and we previously found that alcohol alters actin composition and dendritic spine structure in the nucleus accumbens (NAc) and the dorsomedial striatum (DMS). To examine if Rac1 contributes to these alcohol-mediated adaptations, we measured the level of GTP-bound active Rac1 in the striatum of mice following 7 weeks of intermittent access to 20% alcohol. We found that chronic alcohol intake activates Rac1 in the DMS of male mice. In contrast, Rac1 is not activated by alcohol in the NAc and DLS of male mice, or in the DMS of female mice. Similarly, closely related small G-proteins are not activated by alcohol in the DMS, and Rac1 activity is not increased in the DMS by moderate alcohol or natural reward. To determine the consequences of alcohol-dependent Rac1 activation in the DMS of male mice, we inhibited endogenous Rac1 by infecting the DMS of mice with an AAV expressing a dominant negative form of the small G-protein (Rac1-DN). We found that overexpression of AAV-Rac1-DN in the DMS inhibits alcohol-mediated Rac1 signaling and attenuates alcohol-mediated F-actin polymerization, which corresponded with a decrease in dendritic arborization and spine maturation. Finally, we provide evidence to suggest that Rac1 in the DMS plays a role in alcohol-associated goal-directed learning. Together, our data suggest that Rac1 in the DMS plays an important role in alcohol-dependent structural plasticity and aberrant learning. Addiction, including alcohol use disorder, is characterized by molecular and cellular adaptations that promote maladaptive behaviors. We found that Rac1 was activated by alcohol in the dorsomedial striatum (DMS) of male mice. We show that alcohol-mediated Rac1 signaling is responsible for alterations in actin dynamics and neuronal morphology. We also present data to suggest that Rac1 is important for alcohol-associated learning processes. These results suggest that Rac1 in the DMS is an important contributor to adaptations that promote alcohol use disorder.
PubMed: 38886056
DOI: 10.1523/JNEUROSCI.1644-23.2024 -
Neurobiology of Disease Jun 2024The vagus nerve serves as an interoceptive relay between the body and the brain. Despite its well-established role in feeding behaviors, energy metabolism, and cognitive...
The vagus nerve serves as an interoceptive relay between the body and the brain. Despite its well-established role in feeding behaviors, energy metabolism, and cognitive functions, the intricate functional processes linking the vagus nerve to the hippocampus and its contribution to learning and memory dynamics remain still elusive. Here, we investigated whether and how the gut-brain vagal axis contributes to hippocampal learning and memory processes at behavioral, functional, cellular, and molecular levels. Our results indicate that the integrity of the vagal axis is essential for long-term recognition memories, while sparing other forms of memory. In addition, by combing multi-scale approaches, our findings show that the gut-brain vagal tone exerts a permissive role in scaling intracellular signaling events, gene expressions, hippocampal dendritic spines density as well as functional long-term plasticities (LTD and LTP). These results highlight the critical role of the gut-brain vagal axis in maintaining the spontaneous and homeostatic functions of hippocampal ensembles and in regulating their learning and memory functions. In conclusion, our study provides comprehensive insights into the multifaceted involvement of the gut-brain vagal axis in shaping time-dependent hippocampal learning and memory dynamics. Understanding the mechanisms underlying this interoceptive body-brain neuronal communication may pave the way for novel therapeutic approaches in conditions associated with cognitive decline, including neurodegenerative disorders.
PubMed: 38885849
DOI: 10.1016/j.nbd.2024.106569