Progress in Neurobiology最新文献

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.

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.

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.

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.

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.

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.

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 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.

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.

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.