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Life Science Alliance Sep 2024Schizophrenia is associated with altered cortical circuitry. Although the schizophrenia risk gene is known to affect the wiring of inhibitory interneurons, its role in...
Schizophrenia is associated with altered cortical circuitry. Although the schizophrenia risk gene is known to affect the wiring of inhibitory interneurons, its role in excitatory neurons and axonal development is unclear. Here, we investigated the role of Nrg1 in the development of the corpus callosum, the major interhemispheric connection formed by cortical excitatory neurons. We found that deletion of Nrg1 impaired callosal axon development in vivo. Experiments in vitro and in vivo demonstrated that Nrg1 is cell-autonomously required for axonal outgrowth and that intracellular signaling of Nrg1 is sufficient to promote axonal development in cortical neurons and specifically in callosal axons. Furthermore, our data suggest that Nrg1 signaling regulates the expression of Growth Associated Protein 43, a key regulator of axonal growth. In conclusion, our study demonstrates that NRG1 is involved in the formation of interhemispheric callosal connections and provides a novel perspective on the relevance of NRG1 in excitatory neurons and in the etiology of schizophrenia.
Topics: Animals; Neuregulin-1; Corpus Callosum; Axons; Mice; Signal Transduction; Schizophrenia; Mice, Knockout; Neurons; GAP-43 Protein; Mice, Inbred C57BL
PubMed: 38918041
DOI: 10.26508/lsa.202302250 -
BMC Genomics Jun 2024Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder featured by abnormal movements, arising from the extensive neuronal loss and glial...
Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder featured by abnormal movements, arising from the extensive neuronal loss and glial dysfunction in the striatum. Although the causes and pathogenetic mechanisms of HD are well established, the development of disease-modifying pharmacological therapies for HD remains a formidable challenge. Laduviglusib has demonstrated neuroprotective effects through the enhancement of mitochondrial function in the striatum of HD animal models. Ferroptosis is a nonapoptotic form of cell death that occurs as a consequence of lethal iron-dependent lipid peroxidation and mitochondrial dysfunction. However, the ferroptosis-related mechanisms underlying the neuroprotective effects of laduviglusib in the striatum of HD patients remain largely uncharted. In this study, we leveraged single-nucleus RNA sequencing data obtained from the striatum of HD patients in stages 2-4 to identify differentially expressed genes within distinct cell-type. We subsequently integrated these differentially expressed genes of HD, laduviglusib target genes and ferroptosis-related genes to predict the ferroptosis-related mechanisms underpinning the neuroprotective effects of laduviglusib in HD patients. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses unveiled that the effects of laduviglusib on direct pathway striatal projection neurons (dSPNs) is mainly associated with Th17 cell differentiation pathways. Conversely, its impact on indirect pathway striatal projection neurons (iSPNs) extends to the Neurotrophin signaling pathway, FoxO signaling pathway, and reactive oxygen species pathway. In microglia, laduviglusib appears to contribute to HD pathology via mechanisms related to Th17 cell differentiation and the FoxO signaling pathway. Further, molecular docking results indicated favorable binding of laduviglusib with PARP1 (associated with dSPNs and iSPNs), SCD (associated with astrocytes), ALOX5 (associated with microglia), and HIF1A (associated with dSPNs, iSPNs, and microglia). In addition, the KEGG results suggest that laduviglusib may enhance mitochondrial function and protect against neuronal loss by targeting ferroptosis-related signaling pathways, particularly mediated by ALOX5 in microglia. These findings provide valuable insights into the potential mechanisms through which laduviglusib exerts its effects on distinct cell-types within the HD striatum.
Topics: Ferroptosis; Huntington Disease; Humans; Corpus Striatum; Neuroprotective Agents
PubMed: 38918688
DOI: 10.1186/s12864-024-10534-5 -
Advances in Experimental Medicine and... 2024The human brain is a constructive organ. It generates predictions to modulate its functioning and continuously adapts to a dynamic environment. Increasingly, the... (Review)
Review
The human brain is a constructive organ. It generates predictions to modulate its functioning and continuously adapts to a dynamic environment. Increasingly, the temporal dimension of motor and non-motor behaviour is recognised as a key component of this predictive bias. Nevertheless, the intricate interplay of the neural mechanisms that encode, decode and evaluate temporal information to give rise to a sense of time and control over sensorimotor timing remains largely elusive. Among several brain systems, the basal ganglia have been consistently linked to interval- and beat-based timing operations. Considering the tight embedding of the basal ganglia into multiple complex neurofunctional networks, it is clear that they have to interact with other proximate and distal brain systems. While the primary target of basal ganglia output is the thalamus, many regions connect to the striatum of the basal ganglia, their main input relay. This establishes widespread connectivity, forming the basis for first- and second-order interactions with other systems implicated in timing such as the cerebellum and supplementary motor areas. However, next to this structural interconnectivity, additional functions need to be considered to better understand their contribution to temporally predictive adaptation. To this end, we develop the concept of interval-based patterning, conceived as a temporally explicit hierarchical sequencing operation that underlies motor and non-motor behaviour as a common interpretation of basal ganglia function.
Topics: Humans; Basal Ganglia; Time Perception; Neural Pathways; Animals; Thalamus; Nerve Net
PubMed: 38918357
DOI: 10.1007/978-3-031-60183-5_15 -
Advances in Experimental Medicine and... 2024Timing and motor function share neural circuits and dynamics, which underpin their close and synergistic relationship. For instance, the temporal predictability of a... (Review)
Review
Timing and motor function share neural circuits and dynamics, which underpin their close and synergistic relationship. For instance, the temporal predictability of a sensory event optimizes motor responses to that event. Knowing when an event is likely to occur lowers response thresholds, leading to faster and more efficient motor behavior though in situations of response conflict can induce impulsive and inappropriate responding. In turn, through a process of active sensing, coupling action to temporally predictable sensory input enhances perceptual processing. Action not only hones perception of the event's onset or duration, but also boosts sensory processing of its non-temporal features such as pitch or shape. The effects of temporal predictability on motor behavior and sensory processing involve motor and left parietal cortices and are mediated by changes in delta and beta oscillations in motor areas of the brain.
Topics: Humans; Motor Cortex; Psychomotor Performance; Time Perception; Parietal Lobe; Animals; Motor Activity
PubMed: 38918353
DOI: 10.1007/978-3-031-60183-5_11 -
Advances in Experimental Medicine and... 2024In this chapter, we present recent findings from our group showing that elapsed time, interval timing, and rhythm maintenance might be achieved by the well-known ability... (Review)
Review
In this chapter, we present recent findings from our group showing that elapsed time, interval timing, and rhythm maintenance might be achieved by the well-known ability of the brain to predict the future states of the world. The difference between predictions and actual sensory evidence is used to generate perceptual and behavioral adjustments that help subjects achieve desired behavioral goals. Concretely, we show that (1) accumulating prediction errors is a plausible strategy humans could use to determine whether a train of consecutive stimuli arrives at regular or irregular intervals. By analyzing the behavior of human and non-human primate subjects performing rhythm perception tasks, we demonstrate that (2) the ability to estimate elapsed time and internally maintain rhythms is shared across primates and humans. Neurophysiological recordings show that (3) the medial premotor cortex engages in rhythm entrainment and maintains oscillatory activity that reveals an internal metronome's spatial and temporal characteristics. Finally, we demonstrate that (4) the amplitude of gamma oscillations within this cortex increases proportionally to the total elapsed time. In conjunction with our most recent experiments, our results suggest that timing might be achieved by an internal simulation of the sensory stimuli and the motor commands that define the timing task that needs to be performed.
Topics: Humans; Time Perception; Animals; Motor Cortex; Periodicity
PubMed: 38918351
DOI: 10.1007/978-3-031-60183-5_9 -
Advances in Experimental Medicine and... 2024In rodents and primates, interval estimation has been associated with a complex network of cortical and subcortical structures where the dorsal striatum plays a... (Review)
Review
In rodents and primates, interval estimation has been associated with a complex network of cortical and subcortical structures where the dorsal striatum plays a paramount role. Diverse evidence ranging from individual neurons to population activity has demonstrated that this area hosts temporal-related neural representations that may be instrumental for the perception and production of time intervals. However, little is known about how temporal representations interact with other well-known striatal representations, such as kinematic parameters of movements or somatosensory representations. An attractive hypothesis suggests that somatosensory representations may serve as the scaffold for complex representations such as elapsed time. Alternatively, these representations may coexist as independent streams of information that could be integrated into downstream nuclei, such as the substantia nigra or the globus pallidus. In this review, we will revise the available information suggesting an instrumental role of sensory representations in the construction of temporal representations at population and single-neuron levels throughout the basal ganglia.
Topics: Basal Ganglia; Animals; Humans; Time Perception; Neurons; Sensation
PubMed: 38918350
DOI: 10.1007/978-3-031-60183-5_8 -
Advances in Experimental Medicine and... 2024The measurement of time in the subsecond scale is critical for many sophisticated behaviors, yet its neural underpinnings are largely unknown. Recent neurophysiological... (Review)
Review
The measurement of time in the subsecond scale is critical for many sophisticated behaviors, yet its neural underpinnings are largely unknown. Recent neurophysiological experiments from our laboratory have shown that the neural activity in the medial premotor areas (MPC) of macaques can represent different aspects of temporal processing. During single interval categorization, we found that preSMA encodes a subjective category limit by reaching a peak of activity at a time that divides the set of test intervals into short and long. We also observed neural signals associated with the category selected by the subjects and the reward outcomes of the perceptual decision. On the other hand, we have studied the behavioral and neurophysiological basis of rhythmic timing. First, we have shown in different tapping tasks that macaques are able to produce predictively and accurately intervals that are cued by auditory or visual metronomes or when intervals are produced internally without sensory guidance. In addition, we found that the rhythmic timing mechanism in MPC is governed by different layers of neural clocks. Next, the instantaneous activity of single cells shows ramping activity that encodes the elapsed or remaining time for a tapping movement. In addition, we found MPC neurons that build neural sequences, forming dynamic patterns of activation that flexibly cover all the produced interval depending on the tapping tempo. This rhythmic neural clock resets on every interval providing an internal representation of pulse. Furthermore, the MPC cells show mixed selectivity, encoding not only elapsed time, but also the tempo of the tapping and the serial order element in the rhythmic sequence. Hence, MPC can map different task parameters, including the passage of time, using different cell populations. Finally, the projection of the time varying activity of MPC hundreds of cells into a low dimensional state space showed circular neural trajectories whose geometry represented the internal pulse and the tapping tempo. Overall, these findings support the notion that MPC is part of the core timing mechanism for both single interval and rhythmic timing, using neural clocks with different encoding principles, probably to flexibly encode and mix the timing representation with other task parameters.
Topics: Animals; Time Perception; Motor Cortex; Neurons; Psychomotor Performance
PubMed: 38918349
DOI: 10.1007/978-3-031-60183-5_7 -
Advances in Experimental Medicine and... 2024Temporal information processing in the range of a few hundred milliseconds to seconds involves the cerebellum and basal ganglia. In this chapter, we present recent... (Review)
Review
Temporal information processing in the range of a few hundred milliseconds to seconds involves the cerebellum and basal ganglia. In this chapter, we present recent studies on nonhuman primates. In the studies presented in the first half of the chapter, monkeys were trained to make eye movements when a certain amount of time had elapsed since the onset of the visual cue (time production task). The animals had to report time lapses ranging from several hundred milliseconds to a few seconds based on the color of the fixation point. In this task, the saccade latency varied with the time length to be measured and showed stochastic variability from one trial to the other. Trial-to-trial variability under the same conditions correlated well with pupil diameter and the preparatory activity in the deep cerebellar nuclei and the motor thalamus. Inactivation of these brain regions delayed saccades when asked to report subsecond intervals. These results suggest that the internal state, which changes with each trial, may cause fluctuations in cerebellar neuronal activity, thereby producing variations in self-timing. When measuring different time intervals, the preparatory activity in the cerebellum always begins approximately 500 ms before movements, regardless of the length of the time interval being measured. However, the preparatory activity in the striatum persists throughout the mandatory delay period, which can be up to 2 s, with different rate of increasing activity. Furthermore, in the striatum, the visual response and low-frequency oscillatory activity immediately before time measurement were altered by the length of the intended time interval. These results indicate that the state of the network, including the striatum, changes with the intended timing, which lead to different time courses of preparatory activity. Thus, the basal ganglia appear to be responsible for measuring time in the range of several hundred milliseconds to seconds, whereas the cerebellum is responsible for regulating self-timing variability in the subsecond range. The second half of this chapter presents studies related to periodic timing. During eye movements synchronized with alternating targets at regular intervals, different neurons in the cerebellar nuclei exhibit activity related to movement timing, predicted stimulus timing, and the temporal error of synchronization. Among these, the activity associated with target appearance is particularly enhanced during synchronized movements and may represent an internal model of the temporal structure of stimulus sequence. We also considered neural mechanism underlying the perception of periodic timing in the absence of movement. During perception of rhythm, we predict the timing of the next stimulus and focus our attention on that moment. In the missing oddball paradigm, the subjects had to detect the omission of a regularly repeated stimulus. When employed in humans, the results show that the fastest temporal limit for predicting each stimulus timing is about 0.25 s (4 Hz). In monkeys performing this task, neurons in the cerebellar nuclei, striatum, and motor thalamus exhibit periodic activity, with different time courses depending on the brain region. Since electrical stimulation or inactivation of recording sites changes the reaction time to stimulus omission, these neuronal activities must be involved in periodic temporal processing. Future research is needed to elucidate the mechanism of rhythm perception, which appears to be processed by both cortico-cerebellar and cortico-basal ganglia pathways.
Topics: Animals; Cerebellum; Basal Ganglia; Time Perception; Saccades; Time Factors; Humans
PubMed: 38918348
DOI: 10.1007/978-3-031-60183-5_6 -
Neurology(R) Neuroimmunology &... Sep 2024To evaluate CSF inflammatory markers with accumulation of cortical damage as well as disease activity in patients with early relapsing-remitting MS (RRMS).
BACKGROUND AND OBJECTIVES
To evaluate CSF inflammatory markers with accumulation of cortical damage as well as disease activity in patients with early relapsing-remitting MS (RRMS).
METHODS
CSF levels of osteopontin (OPN) and 66 inflammatory markers were assessed using an immune-assay multiplex technique in 107 patients with RRMS (82 F/25 M, mean age 35.7 ± 11.8 years). All patients underwent regular clinical assessment and yearly 3T MRI scans for 2 years while 39 patients had a 4-year follow-up. White matter lesion number and volume, cortical lesions (CLs) and volume, and global cortical thickness (CTh) were evaluated together with the 'no evidence of disease activity' (NEDA-3) status, defined by no relapses, no disability worsening, and no MRI activity, including CLs.
RESULTS
The random forest algorithm selected OPN, CXCL13, TWEAK, TNF, IL19, sCD30, sTNFR1, IL35, IL16, and sCD163 as significantly associated with changes in global CTh. OPN and CXCL13 were most related to accumulation of atrophy after 2 and 4 years. In a multivariate linear regression model on CSF markers, OPN ( < 0.001), CXCL13 ( = 0.001), and sTNFR1 ( = 0.024) were increased in those patients with accumulating atrophy (adjusted R-squared 0.615). The 10 markers were added in a model that included all clinical, demographic, and MRI variables: OPN ( = 0.002) and IL19 ( = 0.022) levels were confirmed to be significantly increased in patients developing more CTh change over the follow-up (adjusted R-squared 0.619). CXCL13 and OPN also revealed the best association with NEDA-3 after 2 years, with OPN significantly linked to disability accumulation (OR 2.468 [1.46-5.034], = 0.004) at the multivariate logistic regression model.
DISCUSSION
These data confirm and expand our knowledge on the prognostic role of the CSF inflammatory profile in predicting changes in cortical pathology and disease activity in early MS. The data emphasize a crucial role of OPN.
Topics: Humans; Osteopontin; Female; Male; Adult; Multiple Sclerosis, Relapsing-Remitting; Atrophy; Middle Aged; Cerebral Cortex; Magnetic Resonance Imaging; Biomarkers; Follow-Up Studies; Young Adult; Disease Progression
PubMed: 38917380
DOI: 10.1212/NXI.0000000000200265 -
PLoS Biology Jun 2024Low and high beta frequency rhythms were observed in the motor cortex, but their respective sources and behavioral correlates remain unknown. We studied local field...
Low and high beta frequency rhythms were observed in the motor cortex, but their respective sources and behavioral correlates remain unknown. We studied local field potentials (LFPs) during pre-cued reaching behavior in macaques. They contained a low beta band (<20 Hz) dominant in primary motor cortex and a high beta band (>20 Hz) dominant in dorsal premotor cortex (PMd). Low beta correlated positively with reaction time (RT) from visual cue onset and negatively with uninstructed hand postural micro-movements throughout the trial. High beta reflected temporal task prediction, with selective modulations before and during cues, which were enhanced in moments of increased focal attention when the gaze was on the work area. This double-dissociation in sources and behavioral correlates of motor cortical low and high beta, with respect to both task-instructed and spontaneous behavior, reconciles the largely disparate roles proposed for the beta rhythm, by suggesting band-specific roles in both movement control and spatiotemporal attention.
Topics: Animals; Motor Cortex; Attention; Beta Rhythm; Movement; Reaction Time; Macaca mulatta; Male; Cues; Psychomotor Performance
PubMed: 38917200
DOI: 10.1371/journal.pbio.3002670