bioRxiv Subject Collection: Neuroscience's Journal
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Tuesday, October 8th, 2024
| Time |
Event |
| 7:46a |
Molecular states underlying neuronal cell type development and plasticity in the whisker cortex
Mouse whisker somatosensory cortex (wS1) is a major model system to study the experience-dependent plasticity of cortical neuron physiology, morphology, and sensory coding. However, the role of sensory experience in regulating neuronal cell type development and gene expression in wS1 remains poorly understood. We assembled and annotated a transcriptomic atlas of wS1 during postnatal development comprising 45 molecularly distinct neuronal types that can be grouped into eight excitatory and four inhibitory neuron subclasses. Using this atlas, we examined the influence of whisker experience from postnatal day (P) 12, the onset of active whisking, to P22, on the maturation of molecularly distinct cell types. During this developmental period, when whisker experience was normal, [~]250 genes were regulated in a neuronal subclass-specific fashion. At the resolution of neuronal types, we found that only the composition of layer (L) 2/3 glutamatergic neuronal types, but not other neuronal types, changed substantially between P12 and P22. These compositional changes resemble those observed previously in the primary visual cortex (V1), and the temporal gene expression changes were also highly conserved between the two regions. In contrast to V1, however, cell type maturation in wS1 is not substantially dependent on sensory experience, as 10-day full-face whisker deprivation did not influence the transcriptomic identity and composition of L2/3 neuronal types. A one-day competitive whisker deprivation protocol also did not affect cell type identity but induced moderate changes in plasticity-related gene expression. Thus, developmental maturation of cell types is similar in V1 and wS1, but sensory deprivation minimally affects cell type development in wS1.
Highlights- A single-nucleus transcriptomic atlas of the whisker somatosensory cortex (wS1) during early postnatal development
- Different neuronal subclasses in wS1 show distinct developmental gene expression changes
- The composition of L2/3 glutamatergic neurons changes between the second and the third postnatal week
- Developmental gene expression and cell type changes are conserved between wS1 and the primary visual cortex (V1)
- Unlike V1, these changes are not affected by prolonged sensory deprivation
- Brief whisker deprivation induces subclass-specific activity-dependent gene expression in a whisker column-specific fashion | | 10:33a |
Oxytocin Gαi signaling-induced amygdala astrocytes processes retraction shapes behavioral stress response
Anticipated reactions to stressful situations are vital for the survival and well-being of organisms, and abnormal reactions are involved in stress-related disorders. The neuropeptide oxytocin is a key modulator ensuring well-adapted stress responses. Oxytocin acts on both neurons and astrocytes, but the molecular and cellular mechanisms mediating stress response remain poorly understood. Here, we focus on the amygdala, a crucial hub that integrates and processes sensory information through oxytocin- dependent mechanisms. Using an acute stress paradigm in mice, genetic and pharmacological manipulations combined with proteomic, morphological, electrophysiological and behavioral approaches, we reveal that oxytocinergic modulation of the freezing response to stress is mediated by transient Gi-dependent retraction of astrocytic processes, followed by enhanced neuronal sensitivity to extracellular potassium in the amygdala. Our findings elucidate a pivotal role for astrocytes morphology- dependent modulation of brain circuits that is required for proper anticipated behavioral response to stressful situations. | | 10:33a |
TAOK2 Drives Opposing Cilia Length Deficits in 16p11.2 Deletion and Duplication Carriers
Copy number variation (CNV) in the 16p11.2 (BP4-BP5) genomic locus is strongly associated with autism. Carriers of 16p11.2 deletion and duplication exhibit several common behavioral and social impairments, yet, show opposing brain structural changes and body mass index. To determine cellular mechanisms that might contribute to these opposing phenotypes, we performed quantitative tandem mass tag (TMT) proteomics on human dorsal forebrain neural progenitor cells (NPCs) differentiated from induced pluripotent stem cells (iPSC) derived from 16p11.2 CNV carriers. Differentially phosphorylated proteins between unaffected individuals and 16p11.2 CNV carriers were significantly enriched for centrosomal and cilia proteins. Deletion patient-derived NPCs show increased primary cilium length compared to unaffected individuals, while stunted cilium growth was observed in 16p11.2 duplication NPCs. Through cellular shRNA and overexpression screens in human iPSC derived NPCs, we determined the contribution of genes within the 16p11.2 locus to cilium length. TAOK2, a serine threonine protein kinase, and PPP4C, a protein phosphatase, were found to regulate primary cilia length in a gene dosage-dependent manner. We found TAOK2 was localized at centrosomes and the base of the primary cilium, and NPCs differentiated from TAOK2 knockout iPSCs had longer cilia. In absence of TAOK2, there was increased pericentrin at the basal body, and aberrant accumulation of IFT88 at the ciliary distal tip. Further, pharmacological inhibition of TAO kinase activity led to increased ciliary length, indicating that TAOK2 negatively controls primary cilium length through its catalytic activity. These results implicate aberrant cilia length in the pathophysiology of 16p11.2 CNV, and establish the role of TAOK2 kinase as a regulator of primary cilium length. | | 10:33a |
Local cortical inhibitory subnetworks are shaped by pyramidal neuron progenitor type
The degree to which cortical neurons share inhibitory synaptic input determines their co-activity within a network. However, the principles by which inhibition is shared between neurons are not known. Here we combine in utero labeling with in vivo two-photon targeted patch-clamp recordings in mature cortex to reveal that a layer 2/3 (L2/3) pyramidal neurons local inhibitory input reflects the embryonic progenitor type from which the neuron is born. In contrast to neighboring neurons, pyramidal neurons derived from intermediate progenitors receive synaptic inhibition that is weakly coupled to local network activity. The underlying mechanisms do not depend upon the amount of inhibitory input received from different interneuron subclasses. Rather, progenitor type defines how much inhibitory input a neuron shares with its neighbors, which is reflected in how individual interneurons target pyramidal neurons according to progenitor type. These findings reveal new significance for progenitor diversity and identify ontogenetic origins of fine-scale inhibitory cortical subnetworks. | | 10:33a |
Neural mechanisms of the transition from planning to execution in speech production
The neural basis of speech production involves the rapid transition from abstract planning of speech units such as syllables and phonemes, to the motor execution of speech sounds. Although a distributed network of brain regions has been implicated in speech production overall, it is unclear how the brain transitions from planning to execution for speech production. Leveraging the high spatio-temporal resolution of intracranial recordings, we find evidence for neural mechanisms that operate in space and time across the prefrontal and premotor cortices to facilitate the transition from planning to execution. During this execution, we show evidence for motor sequencing from neural activity that tracks both phonological units as well as the transition between them, suggesting both discrete elements from planning as well as continuous motor transitions. We demonstrate temporally-resolved neural mechanisms for the transition between planning and execution to facilitate speech production. | | 10:33a |
Spatiotemporal characterisation of information coding and exchange in the multiple demand network
The multiple-demand network (MDN), a brain-wide system with nodes near sensory and higher-order cognitive regions, has been suggested to integrate and exchange task-related information across the brain, supporting cognitive task performance. However, the profile of information coding and the role of each node within this network in information exchange remain unclear. To address this, we combined fMRI and MEG data in a challenging stimulus-response mapping task. Using multivariate pattern analysis (MVPA), we decoded various forms of task information, including coarse and fine stimulus details, motor responses, and stimulus-response mapping rules, across the MDN and visual regions. Early in the task, visual regions responded to large physical differences in stimuli, while later on, fine stimulus information and rules were encoded across the MDN. To assess information exchange between regions, we developed Fusion-RCA, a novel connectivity analysis method based on fMRI-MEG fusion profiles. Our findings revealed significant transfer of fine stimulus information, rules, and responses, but little evidence for the transfer of coarse stimulus information. These results highlight distinct information encoding patterns within MDN nodes and suggest that the anterior cingulate cortex (ACC) plays a key role in distributing task-relevant information. This study offers new insights into the dynamic function of the MDN and introduces Fusion-RCA as a powerful tool for exploring brain-wide information transfer. | | 10:33a |
Reward and punishment contingency shifting reveals distinct roles for VTA dopamine and GABA neurons in behavioral flexibility
In dynamic environments where stimuli predicting rewarding or aversive outcomes unexpectedly change, it is critical to flexibly update behavior while preserving recollection of previous associations. Dopamine and GABA neurons in the ventral tegmental area (VTA) are implicated in reward and punishment learning, yet little is known about how each population adapts when the predicted outcome valence changes. We measured VTA dopamine and GABA population activity while male and female rats learned to associate three discrete auditory cues to three distinct outcomes: reward, punishment, or no outcome within the same session. After learning, the reward and punishment cue-outcome contingencies were reversed, and subsequently rereversed. As expected, the dopamine population rapidly adapted to learning and contingency reversals by increasing the response to appetitive stimuli and decreasing the response to aversive stimuli. In contrast, the GABA population increased activity to all sensory events regardless of valence, including the neutral cue. Reversing learned contingencies selectively influenced GABA responses to the reward-predictive cue, prolonging increased activity within and across sessions. The observed valence-specific dissociations in the directionality and temporal progression of VTA dopamine and GABA calcium activity indicates that these populations are independently recruited and serve distinct roles during appetitive and aversive associative learning and contingency reversal. | | 10:33a |
Striatal cell-type-specific molecular signatures reveal therapeutic targets in a model of dystonia
Striatal dysfunction is implicated in many forms of dystonia, including idiopathic, inherited and iatrogenic dystonias. The striatum is comprised largely of GABAergic spiny projection neurons (SPNs) that are defined by their long-range efferents. Direct SPNs (dSPNs) project to the internal globus pallidus/substantia nigra reticulata whereas indirect pathway SPNs (iSPNs) project to the external pallidum; the concerted activity of both SPN subtypes modulates movement. Convergent results from genetic, imaging and physiological studies in patients suggest that abnormalities of both dSPNs and iSPNs contribute to the expression of dystonia, but the molecular adaptations underlying these abnormalities are not known. Here we provide a comprehensive analysis of SPN cell-type-specific molecular signatures in a model of DOPA-responsive dystonia (DRD mice), which is caused by gene defects that reduce dopamine neurotransmission, resulting in dystonia that is specifically associated with striatal dysfunction. Individually profiling the translatome of dSPNs and iSPNs using translating ribosome affinity purification with RNA-seq revealed hundreds of differentially translating mRNAs in each SPN subtype in DRD mice, yet there was little overlap between the dysregulated genes in dSPNs and iSPNs. Despite the paucity of shared adaptations, a disruption in glutamatergic signaling was predicted for both dSPNs and iSPNs. Indeed, we found that both AMPA and NMDA receptor-mediated currents were enhanced in dSPNs but diminished in iSPNs in DRD mice. The pattern of mRNA dysregulation was specific to dystonia as the adaptations in DRD mice were distinct from those in parkinsonian mice where the dopamine deficit occurs in adults, suggesting that the phenotypic outcome is dependent on both the timing of the dopaminergic deficit and the SPN-specific adaptions. We leveraged the unique molecular signatures of dSPNs and iSPNs in DRD mice to identify biochemical mechanisms that may be targets for therapeutics, including LRRK2 inhibition. Administration of the LRRK2 inhibitor MLi-2 ameliorated the dystonia in DRD mice suggesting a novel target for therapeutics and demonstrating that the delineation of cell-type-specific molecular signatures provides a powerful approach to revealing both CNS dysfunction and therapeutic targets in dystonia. | | 10:33a |
APOE4 impacts cortical neurodevelopment and alters network formation in human brain organoids
Apolipoprotein E4 (APOE4) is the leading genetic risk factor for Alzheimers disease. While most studies examine the role of APOE4 in aging, imaging, and cognitive assessments reveal that APOE4 influences brain structure and function as early as infancy. Here, we examined human-relevant cellular phenotypes across neurodevelopment using induced pluripotent stem cell (iPSC) derived cortical and ganglionic eminence organoids (COs and GEOs). In COs, we showed that APOE4 decreased BRN2+ and SATB2+ cortical neurons, increased astrocytes and outer radial glia, and was associated with increased cell death and dysregulated GABA-related gene expression. In GEOs, APOE4 accelerated maturation of neural progenitors and neurons. Multi-electrode array recordings in assembloids revealed that APOE4 disrupted network formation and altered response to GABA, resulting in heightened excitability and synchronicity. Together, our data provides new insights into how APOE4 may influence cortical neurodevelopmental processes and network formation in the human brain. | | 10:33a |
Electrical diversity of neurons in sensory cortices
The classification of neuronal types is a complex task with numerous molecular, anatomical, and functional (electrical) features have been identified as informative in discriminating neuronal populations. The functional characterization of neurons has traditionally been carried out with predefined sets of parameters such as firing rate and action potential generation threshold. Here we provide an objective method to choose what parameters are most informative about a neurons functional cell type. Using this method we show that despite the significant molecular and anatomical variability across neurons, functional characterization of neuronal activity identifies 9 and 11 distinct neuronal subpopulations in the upper layers of the somatosensory and visual cortices respectively. This novel classification method will help to unravel the functional (electrophysiological) diversity of cellular classes throughout the nervous system. Further, the thorough comparison between the different classes of cells will provide a solid building block for the study of the sensory cortices. | | 5:47p |
Cholecystokinin-expressing GABA neurons elicit long-term potentiation in the cortical inhibitory synapses and attenuate sound-shock associative memory
Neuronal interactions between inhibitory and excitatory neurons play a pivotal role in regulating the balance of excitation and inhibition in the central nervous system (CNS). Consequently, the efficacy of inhibitory/excitatory synapses profoundly affects neural network processing and overall neuronal functions. Here, we describe a novel form of long-term potentiation (LTP) induced at cortical inhibitory synapses and its behavioral consequences. We show that high-frequency laser stimulation (HFLS) of GABAergic neurons elicit inhibitory LTP (i-LTP) in pyramidal neurons of the auditory cortex (AC). The selective activation of cholecystokinin-expressing GABA (GABACCK) neurons is essential for the formation of HFLS-induced i-LTP, rather than the classical parvalbumin (PV) neurons and somatostatin (SST) neurons. Intriguingly, i-LTP can be evoked in the AC by adding the exogenous neuropeptide CCK when PV neurons and SST neurons are selectively activated in PV-Cre and SST-Cre mice, respectively. Additionally, we discovered that low-frequency laser stimulation (LFLS) of PV neurons paired with HFLS of GABACCK neurons potentiates the inhibitory effect of PV interneurons on pyramidal neurons, thereby generating heterosynaptic i-LTP in the AC. Notably, light activation of GABACCK neurons in CCK-Cre mice significantly attenuates sound-shock associative memory, while stimulation of PV neurons does not affect this memory in PV-Cre mice. In conclusion, these results demonstrate a critical mechanism regulating the excitation-inhibition balance and modulating learning and memory in cortical circuits. This mechanism might serve as a potential target for the treatment of neurological disorders, including epilepsy and Alzheimers disease. | | 6:21p |
Task relevance selectively modulates sensorimotor adaptation in the presence of multiple prediction errors.
Adaptation to consistently occurring sensorimotor errors is considered obligatory in nature. We probed the robustness of this finding by asking if humans can selectively attenuate adaptation based on the task-relevance of error signals. Subjects made planar reaches to three different targets: an arc (Experiment 1), a bar (Experiment 2), and a point (Experiment 3). During the reach, perturbations in extent (visuomotor gain), direction (visuomotor rotation) or both simultaneously were employed. In Experiment 1, subjects showed robust adaptation to the rotation when reaching to the arc even though the presence of this perturbation was irrelevant for achievement of the task goal. Interestingly however, rotation adaptation was strongly attenuated when it was presented simultaneously with a task-relevant gain perturbation. In Experiment 2, which involved reaches to the bar, again, subjects successfully adapted to the task-irrelevant gain perturbation when it occurred in isolation. However, adaptation was attenuated when the gain co-occurred with a task-relevant rotation. Experiment 3 revealed that the attenuation observed in the first two experiments was not due to an inability to adapt to co-occurring rotation and gain perturbations. Collectively, our results suggest that the sensorimotor system selectively tunes learning in the presence of multiple error signals, a finding that can potentially be explained by a biased competition mechanism. That is, given limited processing capacity, a salient attribute - the relevance of the error to the task goal in this case - is prioritized for processing and drives subsequent adaptive changes in motor output.
NEW AND NOTEWORTHYThe motor system continuously uses error feedback to recalibrate movements in response to changes in body and environmental conditions. Such error-based adaptation is thought to be obligatory, occurring whenever error signals are present, and even if the learning interferes with achievement of the task goal. Contrary to this classical view, we demonstrate selective modulation of motor adaptation in the presence of multiple error signals based on their task-relevance. | | 6:21p |
Genetically-encoded markers for confocal visualization of single dense core vesicles
Neuronal dense core vesicles (DCVs) store and release a diverse array of neuromodulators, trophic factors and bioamines. The analysis of single DCVs has largely been possible only using electron microscopy, which makes understanding cargo segregation and DCV heterogeneity difficult. To address these limitations, we developed genetically-encoded markers for DCVs that can be used in combination with standard immunohistochemistry and expansion microscopy, to enable single-vesicle resolution with confocal microscopy. | | 9:47p |
Modeling the Effects of Propofol on Brain Activity: Insights from Computational EEG Studies
The effects of anesthetic agents like propofol on brain activity provide critical insights into how consciousness is altered during anesthesia. This article presents a computational approach to modeling the impact of propofol on the brains electrical activity using the COALIA model, a large-scale neural mass model of human EEG designed for consciousness research. Propofol enhances GABA_A-mediated synaptic inhibition, leading to characteristic EEG signatures such as alpha oscillations (8-12 Hz) and slow-wave oscillations (0.1-1.5 Hz). We model these effects by modulating the parameters of postsynaptic potentials and synaptic strength, simulating the action of propofol at both the molecular and network levels. COALIAs detailed representation of thalamo-cortical and cortico-cortical networks provides realistic simulations of brain dynamics under anesthesia, closely replicating experimental EEG data. Our findings highlight the importance of network-level interactions in producing the distinctive EEG changes seen during propofol-induced unconsciousness. This research paves the way for future applications in personalized anesthesia monitoring and consciousness assessment through EEG modeling. |
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