Progress In Neurobiology[JOURNAL]
Sun
200 papers
The unconditioned fear response in vertebrates deficient in dystrophin.
Gharibi S, Vaillend C, Lindsay A
Prog Neurobiol · 2024 Apr · PMID 38484964 · Publisher ↗
Dystrophin loss due to mutations in the Duchenne muscular dystrophy (DMD) gene is associated with a wide spectrum of neurocognitive comorbidities, including an aberrant unconditioned fear response to stressful/threat sti...
Dystrophin loss due to mutations in the Duchenne muscular dystrophy (DMD) gene is associated with a wide spectrum of neurocognitive comorbidities, including an aberrant unconditioned fear response to stressful/threat stimuli. Dystrophin-deficient animal models of DMD demonstrate enhanced stress reactivity that manifests as sustained periods of immobility. When the threat is repetitive or severe in nature, dystrophinopathy phenotypes can be exacerbated and even cause sudden death. Thus, it is apparent that enhanced sensitivity to stressful/threat stimuli in dystrophin-deficient vertebrates is a legitimate cause of concern for patients with DMD that could impact neurocognition and pathophysiology. This review discusses our current understanding of the mechanisms and consequences of the hypersensitive fear response in preclinical models of DMD and the potential challenges facing clinical translatability.
Fundamentals of sleep regulation: Model and benchmark values for fractal and oscillatory neurodynamics.
Bódizs R, Schneider B, Ujma PP … +3 more , Horváth CG, Dresler M, Rosenblum Y
Prog Neurobiol · 2024 Mar · PMID 38458483 · Publisher ↗
Homeostatic, circadian and ultradian mechanisms play crucial roles in the regulation of sleep. Evidence suggests that ratios of low-to-high frequency power in the electroencephalogram (EEG) spectrum indicate the instanta...
Homeostatic, circadian and ultradian mechanisms play crucial roles in the regulation of sleep. Evidence suggests that ratios of low-to-high frequency power in the electroencephalogram (EEG) spectrum indicate the instantaneous level of sleep pressure, influenced by factors such as individual sleep-wake history, current sleep stage, age-related differences and brain topography characteristics. These effects are well captured and reflected in the spectral exponent, a composite measure of the constant low-to-high frequency ratio in the periodogram, which is scale-free and exhibits lower interindividual variability compared to slow wave activity, potentially serving as a suitable standardization and reference measure. Here we propose an index of sleep homeostasis based on the spectral exponent, reflecting the level of membrane hyperpolarization and/or network bistability in the central nervous system in humans. In addition, we advance the idea that the U-shaped overnight deceleration of oscillatory slow and fast sleep spindle frequencies marks the biological night, providing somnologists with an EEG-index of circadian sleep regulation. Evidence supporting this assertion comes from studies based on sleep replacement, forced desynchrony protocols and high-resolution analyses of sleep spindles. Finally, ultradian sleep regulatory mechanisms are indicated by the recurrent, abrupt shifts in dominant oscillatory frequencies, with spindle ranges signifying non-rapid eye movement and non-spindle oscillations - rapid eye movement phases of the sleep cycles. Reconsidering the indicators of fundamental sleep regulatory processes in the framework of the new Fractal and Oscillatory Adjustment Model (FOAM) offers an appealing opportunity to bridge the gap between the two-process model of sleep regulation and clinical somnology.
Accumulation of NMDA receptors in accumbal neuronal ensembles mediates increased conditioned place preference for cocaine after prolonged withdrawal.
Huai Z, Huang B, He G … +6 more , Li H, Liu Y, Le Q, Wang F, Ma L, Liu X
Prog Neurobiol · 2024 Mar · PMID 38401668 · Publisher ↗
Cue-induced cocaine craving gradually intensifies following abstinence, a phenomenon known as the incubation of drug craving. Neuronal ensembles activated by initial cocaine use, are critically involved in this process....
Cue-induced cocaine craving gradually intensifies following abstinence, a phenomenon known as the incubation of drug craving. Neuronal ensembles activated by initial cocaine use, are critically involved in this process. However, the mechanisms by which neuronal changes occurring in the ensembles after withdrawal contribute to incubation remain largely unknown. Here we labeled neuronal ensembles in the shell of nucleus accumbens (NAcSh) activated by cocaine conditioned place preference (CPP) training. NAcSh ensembles showed an increasing activity induced by CPP test after 21-day withdrawal. Inhibiting synaptic transmission of NAcSh ensembles suppressed the preference for cocaine paired-side after 21-day withdrawal, demonstrating a critical role of NAcSh ensembles in increased preference for cocaine. The density of dendritic spines in dopamine D1 receptor expressing ensembles was increased after 21-day withdrawal. Moreover, the expression of Grin1, a subunit of the N-methyl-D-aspartate (NMDA) receptor, specifically increased in the NAcSh ensembles after cocaine withdrawal in both CPP and self-administration (SA) mouse models. Targeted knockdown or dysfunction of Grin1 in NAcSh ensembles significantly suppressed craving for cocaine. Our results suggest that the accumulation of NMDA receptors in NAcSh ensembles mediates increased craving for cocaine after prolonged withdrawal, thereby providing potential molecular targets for treatment of drug addiction.
Epilepsy and demyelination: Towards a bidirectional relationship.
Li J, Qi H, Chen Y … +1 more , Zhu X
Prog Neurobiol · 2024 Mar · PMID 38378072 · Publisher ↗
Demyelination stands out as a prominent feature in individuals with specific types of epilepsy. Concurrently, individuals with demyelinating diseases, such as multiple sclerosis (MS) are at a greater risk of developing e...
Demyelination stands out as a prominent feature in individuals with specific types of epilepsy. Concurrently, individuals with demyelinating diseases, such as multiple sclerosis (MS) are at a greater risk of developing epilepsy compared to non-MS individuals. These bidirectional connections raise the question of whether both pathological conditions share common pathogenic mechanisms. This review focuses on the reciprocal relationship between epilepsy and demyelination diseases. We commence with an overview of the neurological basis of epilepsy and demyelination diseases, followed by an exploration of how our comprehension of these two disorders has evolved in tandem. Additionally, we discuss the potential pathogenic mechanisms contributing to the interactive relationship between these two diseases. A more nuanced understanding of the interplay between epilepsy and demyelination diseases has the potential to unveiling the molecular intricacies of their pathological relationships, paving the way for innovative directions in future clinical management and treatment strategies for these diseases.
A cytoskeleton symphony: Actin and microtubules in microglia dynamics and aging.
Socodato R, Relvas JB
Prog Neurobiol · 2024 Mar · PMID 38369000 · Publisher ↗
Microglia dynamically reorganize their cytoskeleton to perform essential functions such as phagocytosis of toxic protein aggregates, surveillance of the brain parenchyma, and regulation of synaptic plasticity during neur...
Microglia dynamically reorganize their cytoskeleton to perform essential functions such as phagocytosis of toxic protein aggregates, surveillance of the brain parenchyma, and regulation of synaptic plasticity during neuronal activity bursts. Recent studies have shed light on the critical role of the microtubule cytoskeleton in microglial reactivity and function, revealing key regulators like cyclin-dependent kinase 1 and centrosomal nucleation in the remodeling of microtubules in activated microglia. Concurrently, the role of the actin cytoskeleton is also pivotal, particularly in the context of small GTPases like RhoA, Rac1, and Cdc42 and actin-binding molecules such as profilin-1 and cofilin. This article delves into the intricate molecular landscape of actin and microtubules, exploring their synergistic roles in driving microglial cytoskeletal dynamics. We propose a more integrated view of actin and microtubule cooperation, which is fundamental to understanding the functional coherence of the microglial cytoskeleton and its pivotal role in propelling brain homeostasis. Furthermore, we discuss how alterations in microglial cytoskeleton dynamics during aging and in disease states could have far-reaching implications for brain function. By unraveling the complexities of microglia cytoskeletal dynamics, we can deepen our understanding of microglial functional states and their implications in health and disease, offering insights into potential therapeutic interventions for neurologic disorders.
The multifaceted role of the CXC chemokines and receptors signaling axes in ALS pathophysiology.
La Cognata V, Morello G, Guarnaccia M … +1 more , Cavallaro S
Prog Neurobiol · 2024 Apr · PMID 38367748 · Publisher ↗
Amyotrophic lateral sclerosis (ALS) is a late-onset motor neuron disease with complex genetic basis and still no clear etiology. Multiple intertwined layers of immune system-related dysfunctions and neuroinflammatory mec...
Amyotrophic lateral sclerosis (ALS) is a late-onset motor neuron disease with complex genetic basis and still no clear etiology. Multiple intertwined layers of immune system-related dysfunctions and neuroinflammatory mechanisms are emerging as substantial determinants in ALS onset and progression. In this review, we collect the increasingly arising evidence implicating four main CXC chemokines/cognate receptors signaling axes (CXCR1/2-CXCL1/2/8; CXCR3-CXCL9/10/11; CXCR4/7-CXCL12; CXCR5-CXCL13) in the pathophysiology of ALS. Findings in preclinical models implicate these signaling pathways in motor neuron toxicity and neuroprotection, while in ALS patients dysregulation of CXCLs/CXCRs has been shown at both central and peripheral levels. Immunological monitoring of CXC-ligands in ALS may allow tracking of disease progression, while pharmacological modulation of CXC-receptors provides a novel therapeutic strategy. A deeper understanding of the interplay between CXC-mediated neuroinflammation and ALS is crucial to advance research into treatments for this debilitating uncurable disorder.
Signal peptide peptidase-like 2b modulates the amyloidogenic pathway and exhibits an Aβ-dependent expression in Alzheimer's disease.
Maccioni R, Travisan C, Badman J … +14 more , Zerial S, Wagener A, Andrade-Talavera Y, Picciau F, Grassi C, Chen G, Lemoine L, Fisahn A, Jiang R, Fluhrer R, Mentrup T, Schröder B, Nilsson P, Tambaro S
Prog Neurobiol · 2024 Apr · PMID 38367747 · Publisher ↗
Alzheimer's disease (AD) is a multifactorial disorder driven by abnormal amyloid β-peptide (Aβ) levels. In this study, we investigated the role of presenilin-like signal peptide peptidase-like 2b (SPPL2b) in AD pathophys...
Alzheimer's disease (AD) is a multifactorial disorder driven by abnormal amyloid β-peptide (Aβ) levels. In this study, we investigated the role of presenilin-like signal peptide peptidase-like 2b (SPPL2b) in AD pathophysiology and its potential as a druggable target within the Aβ cascade. Exogenous Aβ42 influenced SPPL2b expression in human cell lines and acute mouse brain slices. SPPL2b and its AD-related substrate BRI2 were evaluated in the brains of App knock-in AD mice and human postmortem AD brains. An early high cortical expression of SPPL2b was observed, followed by a downregulation in late AD pathology in App mice, correlating with synaptic loss. To understand the consequences of pathophysiological SPPL2b dysregulation, we found that SPPL2b overexpression significantly increased APP cleavage, while genetic deletion reduced APP cleavage and Aβ production. Notably, postmortem AD brains showed higher levels of SPPL2b's BRI2 substrate compared to healthy control samples. These results strongly support the involvement of SPPL2b in AD pathology. The early Aβ-induced upregulation of SPPL2b may enhance Aβ production in a vicious cycle, further aggravating Aβ pathology. Therefore, SPPL2b emerges as a potential anti-Aβ drug target.
Contralateral delay activity and alpha lateralization reflect retinotopic and screen-centered reference frames in visual memory.
Mössing WA, Schroeder SCY, Biel AL … +1 more , Busch NA
Prog Neurobiol · 2024 Mar · PMID 38309459 · Publisher ↗
The visual system represents objects in a lateralized manner, with contralateral cortical hemispheres responsible for left and right visual hemifields. This organization extends to visual short-term memory (VSTM), as evi...
The visual system represents objects in a lateralized manner, with contralateral cortical hemispheres responsible for left and right visual hemifields. This organization extends to visual short-term memory (VSTM), as evidenced by electrophysiological indices of VSTM maintenance: contralateral delay activity (CDA) and alpha-band lateralization. However, it remains unclear if VSTM represents object locations in gaze-centered (retinotopic) or screen-centered (spatiotopic) coordinates, especially after eye movements. In two experiments, participants encoded the colors of target objects and made a lateral saccade during the maintenance interval, thereby shifting the object's location on the retina. A non-lateralized probe stimulus was then presented at the new fixation for a change detection task. The CDA maintained lateralization towards the target's original retinotopic location, unaffected by subsequent saccades, and did not invert polarity even when a saccade brought that location into the opposite hemifield. We also found conventional alpha lateralization towards the target's location before a saccade. After a saccade, however, alpha was lateralized towards the screen center regardless of the target's original location, even in a control condition without any memory requirements. This suggests that post-saccadic alpha-band lateralization reflects attentional processes unrelated to memory, while pre- and post-saccade CDA reflect VSTM maintenance in a retinotopic reference frame.
Mesoscale organization of ventral and dorsal visual pathways in macaque monkey revealed by 7T fMRI.
Wang J, Du X, Yao S … +4 more , Li L, Tanigawa H, Zhang X, Roe AW
Prog Neurobiol · 2024 Mar · PMID 38309458 · Publisher ↗
In human and nonhuman primate brains, columnar (mesoscale) organization has been demonstrated to underlie both lower and higher order aspects of visual information processing. Previous studies have focused on identifying...
In human and nonhuman primate brains, columnar (mesoscale) organization has been demonstrated to underlie both lower and higher order aspects of visual information processing. Previous studies have focused on identifying functional preferences of mesoscale domains in specific areas; but there has been little understanding of how mesoscale domains may cooperatively respond to single visual stimuli across dorsal and ventral pathways. Here, we have developed ultrahigh-field 7 T fMRI methods to enable simultaneous mapping, in individual macaque monkeys, of response in both dorsal and ventral pathways to single simple color and motion stimuli. We provide the first evidence that anatomical V2 cytochrome oxidase-stained stripes are well aligned with fMRI maps of V2 stripes, settling a long-standing controversy. In the ventral pathway, a systematic array of paired color and luminance processing domains across V4 was revealed, suggesting a novel organization for surface information processing. In the dorsal pathway, in addition to high quality motion direction maps of MT, MST and V3A, alternating color and motion direction domains in V3 are revealed. As well, submillimeter motion domains were observed in peripheral LIPd and LIPv. In sum, our study provides a novel global snapshot of how mesoscale networks in the ventral and dorsal visual pathways form the organizational basis of visual objection recognition and vision for action.
The Reelin receptor ApoER2 is a cargo for the adaptor protein complex AP-4: Implications for Hereditary Spastic Paraplegia.
Caracci MO, Pizarro H, Alarcón-Godoy C … +9 more , Fuentealba LM, Farfán P, De Pace R, Santibañez N, Cavieres VA, Pástor TP, Bonifacino JS, Mardones GA, Marzolo MP
Prog Neurobiol · 2024 Mar · PMID 38281682 · Full text
Adaptor protein complex 4 (AP-4) is a heterotetrameric complex that promotes export of selected cargo proteins from the trans-Golgi network. Mutations in each of the AP-4 subunits cause a complicated form of Hereditary S...
Adaptor protein complex 4 (AP-4) is a heterotetrameric complex that promotes export of selected cargo proteins from the trans-Golgi network. Mutations in each of the AP-4 subunits cause a complicated form of Hereditary Spastic Paraplegia (HSP). Herein, we report that ApoER2, a receptor in the Reelin signaling pathway, is a cargo of the AP-4 complex. We identify the motif ISSF/Y within the ApoER2 cytosolic domain as necessary for interaction with the canonical signal-binding pocket of the µ4 (AP4M1) subunit of AP-4. AP4E1- knock-out (KO) HeLa cells and hippocampal neurons from Ap4e1-KO mice display increased co-localization of ApoER2 with Golgi markers. Furthermore, hippocampal neurons from Ap4e1-KO mice and AP4M1-KO human iPSC-derived cortical i3Neurons exhibit reduced ApoER2 protein expression. Analyses of biosynthetic transport of ApoER2 reveal differential post-Golgi trafficking of the receptor, with lower axonal distribution in KO compared to wild-type neurons, indicating a role of AP-4 and the ISSF/Y motif in the axonal localization of ApoER2. Finally, analyses of Reelin signaling in mouse hippocampal and human cortical KO neurons show that AP4 deficiency causes no changes in Reelin-dependent activation of the AKT pathway and only mild changes in Reelin-induced dendritic arborization, but reduces Reelin-induced ERK phosphorylation, CREB activation, and Golgi deployment. This work thus establishes ApoER2 as a novel cargo of the AP-4 complex, suggesting that defects in the trafficking of this receptor and in the Reelin signaling pathway could contribute to the pathogenesis of HSP caused by mutations in AP-4 subunits.
Digging into the intrinsic capacity concept: Can it be applied to Alzheimer's disease?
López-Ortiz S, Caruso G, Emanuele E … +8 more , Menéndez H, Peñín-Grandes S, Guerrera CS, Caraci F, Nisticò R, Lucia A, Santos-Lozano A, Lista S
Prog Neurobiol · 2024 Mar · PMID 38266702 · Publisher ↗
Historically, aging research has largely centered on disease pathology rather than promoting healthy aging. The World Health Organization's (WHO) policy framework (2015-2030) underscores the significance of fostering the...
Historically, aging research has largely centered on disease pathology rather than promoting healthy aging. The World Health Organization's (WHO) policy framework (2015-2030) underscores the significance of fostering the contributions of older individuals to their families, communities, and economies. The WHO has introduced the concept of intrinsic capacity (IC) as a key metric for healthy aging, encompassing five primary domains: locomotion, vitality, sensory, cognitive, and psychological. Past AD research, constrained by methodological limitations, has focused on single outcome measures, sidelining the complexity of the disease. Our current scientific milieu, however, is primed to adopt the IC concept. This is due to three critical considerations: (I) the decline in IC is linked to neurocognitive disorders, including AD, (II) cognition, a key component of IC, is deeply affected in AD, and (III) the cognitive decline associated with AD involves multiple factors and pathophysiological pathways. Our study explores the application of the IC concept to AD patients, offering a comprehensive model that could revolutionize the disease's diagnosis and prognosis. There is a dearth of information on the biological characteristics of IC, which are a result of complex interactions within biological systems. Employing a systems biology approach, integrating omics technologies, could aid in unraveling these interactions and understanding IC from a holistic viewpoint. This comprehensive analysis of IC could be leveraged in clinical settings, equipping healthcare providers to assess AD patients' health status more effectively and devise personalized therapeutic interventions in accordance with the precision medicine paradigm. We aimed to determine whether the IC concept could be extended from older individuals to patients with AD, thereby presenting a model that could significantly enhance the diagnosis and prognosis of this disease.
The glymphatic system and Amyotrophic lateral sclerosis.
Eisen A, Nedergaard M, Gray E … +1 more , Kiernan MC
Prog Neurobiol · 2024 Mar · PMID 38266701 · Publisher ↗
The glymphatic system and the meningeal lymphatic vessels provide a pathway for transport of solutes and clearance of toxic material from the brain. Of specific relevance to ALS, this is applicable for TDP-43 and glutama...
The glymphatic system and the meningeal lymphatic vessels provide a pathway for transport of solutes and clearance of toxic material from the brain. Of specific relevance to ALS, this is applicable for TDP-43 and glutamate, both major elements in disease pathogenesis. Flow is propelled by arterial pulsation, respiration, posture, as well as the positioning and proportion of aquaporin-4 channels (AQP4). Non-REM slow wave sleep is the is key to glymphatic drainage which discontinues during wakefulness. In Parkinson's disease and Alzheimer's disease, sleep impairment is known to predate the development of characteristic clinical features by several years and is associated with progressive accumulation of toxic proteinaceous products. While sleep issues are well described in ALS, consideration of preclinical sleep impairment or the potential of a failing glymphatic system in ALS has rarely been considered. Here we review how the glymphatic system may impact ALS. Preclinical sleep impairment as an unrecognized major risk factor for ALS is considered, while potential therapeutic options to improve glymphatic flow are explored.
Caenorhabditis elegans RAC1/ced-10 mutants as a new animal model to study very early stages of Parkinson's disease.
Muñoz-Juan A, Benseny-Cases N, Guha S … +7 more , Barba I, Caldwell KA, Caldwell GA, Agulló L, Yuste VJ, Laromaine A, Dalfó E
Prog Neurobiol · 2024 Mar · PMID 38253120 · Publisher ↗
Patients with Parkinson's disease (PD) display non-motor symptoms arising prior to the appearance of motor signs and before a clear diagnosis. Motor and non-motor symptoms correlate with progressive deposition of the pro...
Patients with Parkinson's disease (PD) display non-motor symptoms arising prior to the appearance of motor signs and before a clear diagnosis. Motor and non-motor symptoms correlate with progressive deposition of the protein alpha-synuclein (Asyn) both within and outside of the central nervous system, and its accumulation parallels neurodegeneration. The genome of Caenorhabditis elegans does not encode a homolog of Asyn, thus rendering this nematode an invaluable system with which to investigate PD-related mechanisms in the absence of interference from endogenous Asyn aggregation. CED-10 is the nematode homolog of human RAC1, a small GTPase needed to maintain the function and survival of dopaminergic neurons against human Asyn-induced toxicity in C. elegans. Here, we introduce C. elegans RAC1/ced-10 mutants as a predictive tool to investigate early PD symptoms before neurodegeneration occurs. Deep phenotyping of these animals reveals that, early in development, they displayed altered defecation cycles, GABAergic abnormalities and an increased oxidation index. Moreover, they exhibited altered lipid metabolism evidenced by the accumulation of lipid droplets. Lipidomic fingerprinting indicates that phosphatidylcholine and sphingomyelin, but not phosphatidylethanolamine or phosphatidylserine, were elevated in RAC1/ced-10 mutant nematodes. These collective characteristics reflect the non-motor dysfunction, GABAergic neurotransmission defects, upregulation of stress response mechanisms, and metabolic changes associated with early-onset PD. Thus, we put forward an easy-to-manipulate preclinical animal model to deepen our understanding of early-stage PD and accelerate the translational path for therapeutic target discovery.
Barrel cortex development lacks a key stage of hyperconnectivity from deep to superficial layers in a rat model of Absence Epilepsy.
Plutino S, Laghouati E, Jarre G … +3 more , Depaulis A, Guillemain I, Bureau I
Prog Neurobiol · 2024 Mar · PMID 38244975 · Publisher ↗
During development of the sensory cortex, the ascending innervation from deep to upper layers provides a temporary scaffold for the construction of other circuits that remain at adulthood. Whether an alteration in this s...
During development of the sensory cortex, the ascending innervation from deep to upper layers provides a temporary scaffold for the construction of other circuits that remain at adulthood. Whether an alteration in this sequence leads to brain dysfunction in neuro-developmental diseases remains unknown. Using functional approaches in a genetic model of Absence Epilepsy (GAERS), we investigated in barrel cortex, the site of seizure initiation, the maturation of excitatory and inhibitory innervations onto layer 2/3 pyramidal neurons and cell organization into neuronal assemblies. We found that cortical development in GAERS lacks the early surge of connections originating from deep layers observed at the end of the second postnatal week in normal rats and the concomitant structuring into multiple assemblies. Later on, at seizure onset (1 month old), excitatory neurons are hyper-excitable in GAERS when compared to Wistar rats. These findings suggest that early defects in the development of connectivity could promote this typical epileptic feature and/or its comorbidities.
Predictable navigation through spontaneous brain states with cognitive-map-like representations.
Li S, Li Z, Liu Q … +4 more , Ren P, Sun L, Cui Z, Liang X
Prog Neurobiol · 2024 Feb · PMID 38232783 · Publisher ↗
Just as navigating a physical environment, navigating through the landscapes of spontaneous brain states may also require an internal cognitive map. Contemporary computation theories propose modeling a cognitive map from...
Just as navigating a physical environment, navigating through the landscapes of spontaneous brain states may also require an internal cognitive map. Contemporary computation theories propose modeling a cognitive map from a reinforcement learning perspective and argue that the map would be predictive in nature, representing each state as its upcoming states. Here, we used resting-state fMRI to test the hypothesis that the spaces of spontaneously reoccurring brain states are cognitive map-like, and may exhibit future-oriented predictivity. We identified two discrete brain states of the navigation-related brain networks during rest. By combining pattern similarity and dimensional reduction analysis, we embedded the occurrences of each brain state in a two-dimensional space. Successor representation modeling analysis recognized that these brain state occurrences exhibit place cell-like representations, akin to those observed in a physical space. Moreover, we observed predictive transitions of reoccurring brain states, which strongly covaried with individual cognitive and emotional assessments. Our findings offer a novel perspective on the cognitive significance of spontaneous brain activity and support the theory of cognitive map as a unifying framework for mental navigation.
Grid codes underlie multiple cognitive maps in the human brain.
Chen D, Axmacher N, Wang L
Prog Neurobiol · 2024 Feb · PMID 38232782 · Publisher ↗
Grid cells fire at multiple positions that organize the vertices of equilateral triangles tiling a 2D space and are well studied in rodents. The last decade witnessed rapid progress in two other research lines on grid co...
Grid cells fire at multiple positions that organize the vertices of equilateral triangles tiling a 2D space and are well studied in rodents. The last decade witnessed rapid progress in two other research lines on grid codes-empirical studies on distributed human grid-like representations in physical and multiple non-physical spaces, and cognitive computational models addressing the function of grid cells based on principles of efficient and predictive coding. Here, we review the progress in these fields and integrate these lines into a systematic organization. We also discuss the coordinate mechanisms of grid codes in the human entorhinal cortex and medial prefrontal cortex and their role in neurological and psychiatric diseases.
Tdrd3-null mice show post-transcriptional and behavioral impairments associated with neurogenesis and synaptic plasticity.
Zhu X, Joo Y, Bossi S … +17 more , McDevitt RA, Xie A, Wang Y, Xue Y, Su S, Lee SK, Sah N, Zhang S, Ye R, Pinto A, Zhang Y, Araki K, Araki M, Morales M, Mattson MP, van Praag H, Wang W
Prog Neurobiol · 2024 Feb · PMID 38216113 · Full text
The Topoisomerase 3B (Top3b) - Tudor domain containing 3 (Tdrd3) protein complex is the only dual-activity topoisomerase complex that can alter both DNA and RNA topology in animals. TOP3B mutations in humans are associat...
The Topoisomerase 3B (Top3b) - Tudor domain containing 3 (Tdrd3) protein complex is the only dual-activity topoisomerase complex that can alter both DNA and RNA topology in animals. TOP3B mutations in humans are associated with schizophrenia, autism and cognitive disorders; and Top3b-null mice exhibit several phenotypes observed in animal models of psychiatric and cognitive disorders, including impaired cognitive and emotional behaviors, aberrant neurogenesis and synaptic plasticity, and transcriptional defects. Similarly, human TDRD3 genomic variants have been associated with schizophrenia, verbal short-term memory and educational attainment. However, the importance of Tdrd3 in normal brain function has not been examined in animal models. Here we generated a Tdrd3-null mouse strain and demonstrate that these mice display both shared and unique defects when compared to Top3b-null mice. Shared defects were observed in cognitive behaviors, synaptic plasticity, adult neurogenesis, newborn neuron morphology, and neuronal activity-dependent transcription; whereas defects unique to Tdrd3-deficient mice include hyperactivity, changes in anxiety-like behaviors, olfaction, increased new neuron complexity, and reduced myelination. Interestingly, multiple genes critical for neurodevelopment and cognitive function exhibit reduced levels in mature but not nascent transcripts. We infer that the entire Top3b-Tdrd3 complex is essential for normal brain function, and that defective post-transcriptional regulation could contribute to cognitive and psychiatric disorders.
ABHD6 drives endocytosis of AMPA receptors to regulate synaptic plasticity and learning flexibility.
Wei M, Yang L, Su F … +10 more , Liu Y, Zhao X, Luo L, Sun X, Liu S, Dong Z, Zhang Y, Shi YS, Liang J, Zhang C
Prog Neurobiol · 2024 Feb · PMID 38159878 · Publisher ↗
Trafficking of α-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors (AMPARs), mediated by AMPAR interacting proteins, enabled neurons to maintain tuning capabilities at rest or active state. α/β-Hydrolas...
Trafficking of α-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors (AMPARs), mediated by AMPAR interacting proteins, enabled neurons to maintain tuning capabilities at rest or active state. α/β-Hydrolase domain-containing 6 (ABHD6), an endocannabinoid hydrolase, was an AMPAR auxiliary subunit found to negatively regulate the surface delivery of AMPARs. While ABHD6 was found to prevent AMPAR tetramerization in endoplasmic reticulum, ABHD6 was also reported to localize at postsynaptic site. Yet, the role of ABHD6 interacting with AMPAR at postsynaptic site, and the physiological significance of ABHD6 regulating AMPAR trafficking remains elusive. Here, we generated the ABHD6 knockout (ABHD6) mice and found that deletion of ABHD6 selectively enhanced AMPAR-mediated basal synaptic responses and the surface expression of postsynaptic AMPARs. Furthermore, we found that loss of ABHD6 impaired hippocampal long-term depression (LTD) and synaptic downscaling in hippocampal synapses. AMPAR internalization assays revealed that ABHD6 was essential for neuronal activity-dependent endocytosis of surface AMPARs, which is independent of ABHD6's hydrolase activity. The defects of AMPAR endocytosis and LTD are expressed as deficits in learning flexibility in ABHD6 mice. Collectively, we demonstrated that ABHD6 is an endocytic accessory protein promoting AMPAR endocytosis, thereby contributes to the formation of LTD, synaptic downscaling and reversal learning.
Phase of neural oscillations as a reference frame for attention-based routing in visual cortex.
Aboutorabi E, Baloni Ray S, Kaping D … +3 more , Shahbazi F, Treue S, Esghaei M
Prog Neurobiol · 2024 Feb · PMID 38142770 · Publisher ↗
Selective attention allows the brain to efficiently process the image projected onto the retina, selectively focusing neural processing resources on behaviorally relevant visual information. While previous studies have d...
Selective attention allows the brain to efficiently process the image projected onto the retina, selectively focusing neural processing resources on behaviorally relevant visual information. While previous studies have documented the crucial role of the action potential rate of single neurons in relaying such information, little is known about how the activity of single neurons relative to their neighboring network contributes to the efficient representation of attended stimuli and transmission of this information to downstream areas. Here, we show in the dorsal visual pathway of monkeys (medial superior temporal area) that neurons fire spikes preferentially at a specific phase of the ongoing population beta (∼20 Hz) oscillations of the surrounding local network. This preferred spiking phase shifts towards a later phase when monkeys selectively attend towards (rather than away from) the receptive field of the neuron. This shift of the locking phase is positively correlated with the speed at which animals report a visual change. Furthermore, our computational modeling suggests that neural networks can manipulate the preferred phase of coupling by imposing differential synaptic delays on postsynaptic potentials. This distinction between the locking phase of neurons activated by the spatially attended stimulus vs. that of neurons activated by the unattended stimulus, may enable the neural system to discriminate relevant from irrelevant sensory inputs and consequently filter out distracting stimuli information by aligning the spikes which convey relevant/irrelevant information to distinct phases linked to periods of better/worse perceptual sensitivity for higher cortices. This strategy may be used to reserve the narrow windows of highest perceptual efficacy to the processing of the most behaviorally relevant information, ensuring highly efficient responses to attended sensory events.
Dissecting neural circuits from rostral ventromedial medulla to spinal trigeminal nucleus bidirectionally modulating craniofacial mechanical sensitivity.
Xue Y, Mo S, Li Y … +3 more , Cao Y, Xu X, Xie Q
Prog Neurobiol · 2024 Jan · PMID 38142769 · Publisher ↗
Chronic craniofacial pain is intractable and its mechanisms remain unclarified. The rostral ventromedial medulla (RVM) plays a crucial role in descending pain facilitation and inhibition. It is unclear how the descending...
Chronic craniofacial pain is intractable and its mechanisms remain unclarified. The rostral ventromedial medulla (RVM) plays a crucial role in descending pain facilitation and inhibition. It is unclear how the descending circuits from the RVM to spinal trigeminal nucleus (Sp5) are organized to bidirectionally modulate craniofacial nociception. We used viral tracing, in vivo optogenetics, calcium signaling recording, and chemogenetic manipulations to investigate the structure and function of RVM-Sp5 circuits. We found that most RVM neurons projecting to Sp5 were GABAergic or glutamatergic and facilitated or inhibited craniofacial nociception, respectively. Both GABAergic interneurons and glutamatergic projection neurons in Sp5 received RVM inputs: the former were antinociceptive, whereas the latter were pronociceptive. Furthermore, we demonstrated activation of both GABAergic and glutamatergic Sp5 neurons receiving RVM inputs in inflammation- or dysfunction-induced masseter hyperalgesia. Activating GABAergic Sp5 neurons or inhibiting glutamatergic Sp5 neurons that receive RVM projections reversed masseter hyperalgesia. Our study identifies specific cell types and projections of RVM-Sp5 circuits involved in facilitating or inhibiting craniofacial nociception respectively. Selective manipulation of RVM-Sp5 circuits can be used as potential treatment strategy to relieve chronic craniofacial muscle pain.
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