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Temporally Coordinated Activity among Motor Cortex, Thalamus, and Thalamic Reticular Nucleus Neurons during Rat Forelimb Movements
Thalamic reticular nucleus (TRN) neurons receive excitatory inputs from both cortical and thalamic neurons and, in turn, inhibit thalamic relay neurons, thereby modulating thalamocortical signaling. Recent studies suggested that the TRN in the motor system contributes to precise temporal control within the cortico-thalamo-cortical loop. However, few studies have examined how TRN neurons temporally coordinate with cortical and thalamic neurons during discrete limb movements. Here, we investigated how TRN neurons collaborate with other neurons during forelimb movements depending on task demands. We trained head-fixed rats (male and female) to perform a forelimb lever-pull task at one of the two difficulty levels (low- or high-demand task group). Spike activity was recorded from TRN neurons, some identified optogenetically, and from neurons in the primary motor cortex and ventral thalamus during task performance. Among these neurons, putative excitatory cortical neurons had the highest proportion of tonic spike activity before lever pull (Hold-type) and the lowest proportion of phasic pull-related activity (Pull-type), with the highest directional specificity. In contrast, TRN neurons exhibited more frequent Pull-type activity with lower directional specificity. Furthermore, rats in the high-demand group adopted a more uniform and robust strategy compared with those in the low-demand group. Notably, TRN neurons showed the greatest adaptive-like activity differences in association with task demands among those neurons: the proportion of Pull-type neurons was higher, and their activity was greater, earlier, and more direction-specific. These results suggest that TRN neurons in the cortico-thalamo-cortical loop play a crucial role in dynamically controlling movements by adapting to circumstances.
The Parafascicular Role in Updating Action from a Spatial to a Visual Strategy Is Driven by Its Glutamatergic Mesencephalic Locomotor Region Inputs
The ability to update actions depends on the thalamus's parafascicular nucleus (PF); however, which PF's inputs control this function is unknown. Here, using fiber photometry, retrograde labeling, ex vivo electrophysiology, and optogenetic manipulations, we identify the contribution of the PF and its glutamatergic inputs to the update from a spatial to a visually guided strategy in a set-shifting task conducted in mice (of either sex). Our results show the following: (1) GCaMP signals from the PF recorded along the update from a spatial to a visual strategy correlate with the probability of selecting the correct action based on a light stimulus. (2) Optogenetic inhibition of the PF during this update decreases the probability of selecting the correct action. (3) The mesencephalic locomotor region (MLR) was found to have the highest probability of synaptic connections with the PF. (4) GCaMP recordings from the MLR→PF input support it as a main driver in allowing the PF update function. (5) Inhibition of the MLR→PF connection decreases the probability of updating the contingency. These findings identify the inputs from the MLR as a crucial driver of the PF's role in controlling the update of actions.
Corticotropin-Releasing Factor and Somatostatin Neurons in the Central Amygdala Mediate Dynamic Defensive Behaviors during Fear Extinction
Traumatic experiences can result in heightened fear responses to trauma-associated stimuli. These symptoms can be difficult to extinguish, so identifying neuronal targets for facilitating fear extinction is critical. Many studies investigating fear learning in mice measure conditioned fear via freezing, but other defensive behaviors, such as flight, can also be present during conditioning. The central amygdala (CEA) mediates conditioned freezing and flight responses via corticotropin-releasing factor-positive (CRF+) and somatostatin-positive (SOM+) neuron populations. However, it is unknown how these populations regulate changes in freezing and flight responses as fear extinction is learned. Thus, we investigated the roles of CRF+ and SOM+ CEA neurons in modulating defensive behaviors during extinction. To elicit dynamic defensive responses in male and female mice, we used a modified pavlovian conditioned flight paradigm that paired an aversive footshock with a serial compound stimulus (SCS) consisting of tone followed by white noise (WN), resulting in freezing during the tone that rapidly transitioned into flight (escape jumping and darting) during WN. We used optogenetics in CRF-Cre and SOM-Cre mice to selectively excite and inhibit CRF+ and SOM+ CEA populations during WN presentation within extinction. Within early extinction, CRF+ inhibition reduced WN-evoked jumping and led to subsequent context-specific reduction in tone-evoked freezing. During extinction, SOM+ excitation replaced early WN-evoked flight with freezing, and both SOM+ excitation and inhibition reduced WN-evoked darting. Collectively, these data demonstrate modulation of jumping and darting behaviors within extinction via CRF+ and SOM+ CEA activity. These findings suggest mechanisms of attenuating multiple defensive behaviors during extinction.
Dopamine Dynamics in the Nucleus Accumbens Reflect Confidence in Detecting the Occurrence and Nonoccurrence of Visual Signals in Perceptual Decision-Making
Dopamine (DA) is critically involved in processes such as reward anticipation, attention, and decision-making. The present study examined the temporal dynamics of phasic DA transients in the nucleus accumbens core (NAcC) during a visual decisional task based on signal detection theory, using the fluorescent DA sensor dLight1.3b. During the decision-making phase, DA transients in the NAcC encoded real-time outcome expectancy, apparently reflecting the confidence of male rats in their choices. Reward prediction errors (RPEs) emerged following reward delivery and omission and were amplified under conditions of increased uncertainty, produced by either degrading the visual target or introducing interfering distraction. Moreover, DA transients were elicited on both visual signal and no-signal trials. These findings demonstrate that DA fluctuations in the NAcC reflect the RPE that incorporates confidence and levels of uncertainty, emphasizing an involvement of nucleus accumbens DA in adaptive decision-making.
Synergetic Relay of Oxygen Transfer and Benzene-Ring-Opening Processes for Efficient Dechlorination Reactions
Biosynthesis of Xyloketals: Furanochromene Skeleton Formed via Heterodimerization of Two Orsellinic Acid-Branched Metabolites
Distinct Hippocampal Mechanisms Support Concept Formation and Updating
Learning systems must constantly decide whether to create new representations or update existing ones. For example, a child learning that a bat is a mammal and not a bird would be best served by creating a new representation, whereas updating may be best when encountering a second similar bat. Characterizing the neural dynamics that underlie these complementary memory operations requires identifying the exact moments when each operation occurs. We address this challenge by interrogating human fMRI brain activation (13 females and 12 males) with a computational learning model that predicts trial-by-trial when memories are created versus updated. We found distinct neural engagement in anterior hippocampus and ventral striatum for model-predicted memory create and update events during early learning. Notably, the degree of this effect in hippocampus, but not ventral striatum, significantly related to learning outcome. Hippocampus additionally showed distinct patterns of functional coactivation with ventromedial prefrontal cortex and angular gyrus during memory creation and premotor cortex during memory updating. These findings suggest that complementary memory functions, as formalized in computational learning models, underlie the rapid formation of novel conceptual knowledge, with the hippocampus and its interactions with frontoparietal circuits playing a crucial role in successful learning.
Functional Clusters for Shape, Texture, and Motion Encoding in Macaque V2
Macaque primary visual cortex (V1) exhibits exquisite columnar organization, while midlevel area V4 does not. Here we investigated the functional organization and representational bases of intervening area V2 in three macaques (one male, two females) with high-density Neuropixels recordings and a variety of visual stimuli—shape, texture, drifting grating, and translational motion patches. We observed dense clusters of similarly tuned neurons often spanning ∼500 µm, consistent with a columnar structure. In terms of representational bases, V2 responses were largely explained by stimulus features based on local image statistics: shape tuning is well modeled by a linear combination of orientation filters, and direction selectivity is stronger with surface compared with object motion, in striking contrast to V4. Overall, our results support the progression from columns to sparse clusters as neuronal representations transform from encoding local features and feature conjunctions in V1/V2 to a high-dimensional object-based code in V4.
When career anxiety becomes gameplay: lessons from China’s ‘young-faculty simulator’
The Pro- But Not Antinociceptive Effects of Cannabidiol Depend on Trpa1b in Larval Zebrafish
The promiscuous ligand cannabidiol (CBD) shows promise as an analgesic, but its complex pharmacodynamics make it difficult to identify its mechanism(s) of action. Putative CBD receptors including cannabinoid receptors CB1 and CB2, as well as Trpv1 and Trpa1—the receptors for capsaicin and mustard oil (AITC), respectively—have been proposed to contribute to CBD-mediated analgesia. Larval zebrafish have several attributes that lend themselves to inquiries into the biology of nociception. The neural circuits underlying nociception in zebrafish larvae are highly analogous to those found in higher vertebrates. Notably, the small size and optical clarity of zebrafish enable holistic evaluation of analgesic function utilizing behavioral and imaging platforms. We report that in larval zebrafish of either sex, CBD serves both anti- and pronociceptive functions. Utilizing place aversion assays as a proxy for nociception, we found that low concentrations of CBD inhibit aversion to noxious chemical stimuli including AITC and acetic acid. Counterintuitively, we found that higher concentrations of CBD potentiated nocifensive behavior as measured by enhanced thermal aversion and increased locomotion. Knockout of Trpa1b eliminated the algogenic effects of CBD while having no effect on its analgesic properties, as it abolished trpa1b + sensory neuron responses to CBD, CBD-evoked thermal hypersensitivity, and increased locomotion in Trpa1b-null animals. Strikingly, CBD profoundly inhibited thermal aversion to noxious heat in Trpa1b-null animals but not in wild-type animals, indicating that CBD-mediated Trpa1b activation can oppose the analgesic properties of CBD. These studies provide a framework to investigate the genetic and neural substrates of CBD-mediated analgesia and nociception.
Artemis II relied on European science: what that means for the region’s space ambitions
Briefing Chat: The tongue trick that helps sunbirds suck
Early Development of Direction Selectivity in the Higher Visual Cortex
A fundamental aspect of visual motion processing is the computation of motion direction. In ferrets, as in primates, selectivity for motion direction is found both in early cortical stages like the primary visual cortex (V1) and in higher visual areas like the middle temporal area in primates and the posteromedial lateral suprasylvian (PMLS) area in ferrets. Little is known about how this critical tuning function develops in higher visual cortex. Here, by studying the development of the ferret's motion pathway, we first reveal the surprising finding that direction selectivity (DS) develops earlier in PMLS than in V1, contrary to the areas’ hierarchical positions. Our data, collected in animals of either sex, furthermore show that while DS is sensitive to visual experience in both areas, the sensitivity profile differs between them: presentation of drifting gratings, containing the full complement of spatial and temporal cues generated by visual motion, can promote DS development in V1 and PMLS. In contrast, flashing stationary stimuli, which lack the spatial displacement of moving stimuli and only contain temporal changes, induce DS only in PMLS, not V1. Collectively our findings reveal significant deviations in PMLS development from that in V1, which will be important to account for in models of motion pathway development and of the developmental disorders that affect this pathway. The complex pattern of relative PMLS and V1 development also highlights the need to address interactions between areas in developmental research.
Daily briefing: AI spread information about an obviously made-up disease
Ribosomal Profiling of the Geniculate Ganglion Identifies the Receptor ALK as Critical for the Development and Maintenance of Oral Sensory Neurons
The geniculate ganglion (GG) consists of two populations of neurons, sensory neurons that innervate the oral cavity and express the transcription factor Phox2b and somatosensory neurons that innervate the pinna and express Brn3a . To identify signaling pathways necessary for oral sensory neuron development and physiology, the translatome of Phox2b + GG neurons was selectively profiled using the RiboTag method. From this analysis, anaplastic lymphoma kinase (ALK) was identified as one of the most highly enriched tyrosine kinase receptors. In situ hybridization revealed that Alk was expressed in nearly all Phox2b + neurons and was absent from Phox2b − neurons. Alk was robustly expressed in GG at all ages examined, from Embryonic Day 14.5 into adulthood. To determine whether Alk is necessary for development of the peripheral gustatory system, GG and taste buds (TBs) from Postnatal Day 3 (P3), P14, and P30 Alk −/− and Alk +/+ male and female mice were examined. Neither oral sensory neurons (PHOX2B + ) nor total GG neurons (TUJ1 + ) died in Alk −/− mice. However, TB number, volume, and innervation were all significantly decreased in Alk −/− mice, as compared with Alk +/+ mice. ALK mutations cause a portion of nonsmall cell lung cancers, and treatment with ALK inhibitors, such as ceritinib, frequently causes dysgeusia. Mice receiving ceritinib for 30 d showed a dramatic reduction in TB volume and innervation, as compared with vehicle-treated controls. Somal diameters of oral sensory neurons atrophied and a significant portion of PHOX2B + neurons died in ceritinib-treated mice. ALK is thus critical for development and maintenance of oral sensory neurons.
Vapor-Induced Negative Expansion of Porous Cross-Linked Polymers Observed by Optical Resonance
MTCL2 Is Essential for the Bipolar-to-Multipolar Transition in the Dendrite Extension of Cerebellar Granule Neurons
The dynamic regulation of neuronal polarity is essential for the formation of neural networks during brain development. Primary cultures of rodent neurons recapitulate several aspects of this polarity regulation, providing valuable insights into the molecular mechanisms underlying axon specification, dendrite formation, and neuronal migration. However, the process by which the preexisting bipolarity of migrating neurons is disrupted to form multipolar dendrites remains to be elucidated. In this study, we demonstrate that MTCL2, a microtubule-crosslinking protein associated with the Golgi apparatus, plays a crucial role in this type of polarity transformation exhibited by cerebellar granule neurons (CGNs) in mice of either sex. MTCL2 is highly expressed in CGNs and gradually accumulates in dendrites as the cells develop polarity. MTCL2 knockdown inhibited the bipolar-to-multipolar transition of dendrite extension observed in their differentiation in vitro as well as in vivo. During this transformation, the Golgi apparatus shifts from the base of the preexisting bipolar neurites to the lateral or apical side of the nucleus in the cell body. There, it forms a close association with the microtubule cage that wraps around the nucleus. The resulting upward extension of the Golgi apparatus is tightly coupled with the randomization of its position in the x – y plane. Knockdown and rescue experiments demonstrated MTCL2 promotes these changes in the Golgi position in a microtubule- and Golgi-binding activity-dependent manner. These results suggest that MTCL2 promotes the development of multipolar short dendrites by sequestering the Golgi apparatus from the base of the preexisting neurite into the microtubule cage.