bioRxiv Subject Collection: Neuroscience's Journal
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Tuesday, May 7th, 2024
| Time |
Event |
| 12:48a |
Psilocybin facilitates fear extinction: importance of dose, context, and serotonin receptors
A variety of classic psychedelics and MDMA have been shown to enhance fear extinction in rodent models. This has translational significance because a standard treatment for posttraumatic stress disorder (PTSD) is prolonged exposure therapy. However, few studies have investigated psilocybin's potential effect in fear learning paradigms. More specifically, the extents to which dose, timing of administration, and serotonin receptors may influence psilocybin's effect on fear extinction are not understood. In this study, we used a delay fear conditioning paradigm to determine the effects of psilocybin on fear extinction, extinction retention, and fear renewal in male and female mice. Psilocybin robustly enhances fear extinction when given acutely prior to testing for all doses tested. Psilocybin also exerts long-term effects to elevate extinction retention and suppress fear renewal in a novel context, though these changes were sensitive to dose. Administration of psilocybin prior to fear learning or immediately after extinction yielded no change in behavior, indicating that concurrent extinction experience is necessary for the drug's effects. Co-treatment with a 5-HT2A receptor antagonist blocked psilocybin's effects for extinction, extinction retention and fear renewal, whereas 5-HT1A receptor antagonism attenuated only the effect on fear renewal. Collectively, these results highlight dose, context, and serotonin receptors as crucial factors in psilocybin's ability to facilitate fear extinction. The study provides preclinical evidence to support investigating psilocybin as a pharmacological adjunct for extinction-based therapy for PTSD. | | 11:35a |
Episodic memory supports the acquisition of structured task representations
Generalization to new tasks requires learning of task representations that accurately reflect the similarity structure of the task space. Here, we argue that episodic memory (EM) plays an essential role in this process by stabilizing task representations, thereby supporting the accumulation of structured knowledge. We demonstrate this using a neural network model that infers task representations that minimize the current task's objective function; crucially, the model can retrieve previously encoded task representations from EM and use these to initialize the task inference process. With EM, the model succeeds in learning the underlying task structure; without EM, task representations drift and the network fails to learn the structure. We further show that EM errors can support structure learning by promoting the activation of similar task representations in tasks with similar sensory inputs. Overall, this model provides a novel account of how EM supports the acquisition of structured task representations. | | 11:35a |
Helping behavior is associated with increased affiliative behavior, activation of the prosocial brain network and elevated oxytocin receptor expression in the nucleus accumbens
A prosocial response to others in distress is increasingly recognized as a natural behavior for many social species, from humans to rodents. While prosocial behavior is more frequently observed towards familiar conspecifics, even within the same social context some individuals are more prone to help than others. For instance, in a rat helping behavior test, rats can release a distressed conspecific trapped inside a restrainer by opening the restrainer door. Typically, rats are motivated to release a trapped cagemate, and consistently release the trapped rat ('openers'), yet around 30% do not open the restrainer ('non-openers'). To characterize the difference between these populations, behavioral and neural activity were compared between opener and non-opener rats tested with a trapped cagemate in the helping test. Behaviorally, openers showed significantly more social affiliative behavior both before and after door-opening compared to non-openers. Analysis of brain-wide neural activity based on the immediate early gene c-Fos revealed increased activity in openers in the previously identified prosocial neural network compared to non-openers. The network includes regions associated with empathy in humans (somatosensory cortex, insula, cingulate cortex and frontal cortex), and motivation and reward regions such as the nucleus accumbens. Oxytocin receptor mRNA expression levels were higher in the accumbens but not the anterior insula. Several transcription control pathways were also significantly upregulated in openers' accumbens. These findings indicate that prosocial behavior may be predicted by affiliative behavior and activity in the prosocial neural network and provide targets for the investigation of causal mechanisms underlying prosocial behavior. | | 2:16p |
PrediRep: Modelling hierarchical predictive coding with an unsupervised deep learning network
Hierarchical predictive coding (hPC) proposes that the cortex continuously generates predictions of incoming sensory stimuli. Deep neural networks inspired by hPC are frequently used to probe the neurocomputational mechanisms suggested by the theory in silico and to generate hypotheses for experimental investigations. However, these networks often deviate from hPC by prioritizing computational efficiency over alignment with its principles. To remedy this, we introduce PrediRep, a deep learning model explicitly designed to emphasize alignment with the theory. PrediRep incorporates the principles of hPC found in the other networks, while avoiding their deviations from it. We evaluate the performance of PrediRep on a next-frame prediction task and its functional alignment with hPC, comparing it to other contemporary deep learning networks inspired by the theory. Our findings demonstrate that PrediRep achieves the closest functional alignment with hierarchical predictive coding without sacrificing computational performance. | | 5:48p |
Singular Odorant Receptor Expression Orchestrated by Promoter Activation Specificity in Apis Mellifera Olfactory Sensory Neurons
Honeybee, positioned as an outgroup of flies and mosquitos, have exhibited intriguing duplications and expansions of OR genes in genomic studies. However, little is known about how the OR genes are expressed and regulated in honeybee olfactory sensory neurons (OSNs). In this study, we utilized a single-cell multi-omics approach to profile the transcriptome and chromatin accessibility in Apis mellifera antennal nuclei, aiming to elucidate OR gene expression and its underlying regulatory mechanisms. Our systematical analysis unveiled a similar singular expression pattern of ligand-specific receptors in Apis mellifera OSNs, parallel with those observed in Drosophila melanogaster. Mechanistically, we discovered that promoter activation of OR genes orchestrates receptor expression patterns. For instance, although multiple adjacent OR genes are co-expressed with a single active promoter through polycistronic transcription, only the first OR gene could produce functional receptor protein, as supported by transcriptome quantification in OSNs. Additionally, we found that co-expression of receptor proteins might occur only when co-expressed OR genes possess multiple accessible promoters. This scenario is less common than expected, considering the number and evolutionary age of OR genes in Apis mellifera, suggesting a selection favoring the specialization of rapidly expanded OR genes in Apis mellifera. Overall, our study provides significant insights into the insect olfaction system and the regulatory mechanisms of OR genes expression. | | 6:16p |
Influence of environmental and biological factors on functional connectivity of the superior temporal sulcus in neonates scanned at term age
The superior temporal sulcus (STS), one of the first sulci visible during brain development, is a key region for human communication, notably hosting linguistic functions in the left hemisphere. Fetuses and premature newborns already process external sound, but the auditory environment is vastly different in-utero and ex-utero. Does this have an impact on the development of the auditory and linguistic networks? To answer this question, we studied the functional connectivity of regions bordering the STS, delimited in each individual including full-term and preterm male and female neonates born at different gestational ages but all scanned at term. We found that in addition to the expected contralateral connectivity, various STS parts were more strongly connected to specific distant regions, revealing the typical auditory/linguistic division across the two banks of the STS reported in adults. Furthermore, the right posterior STS was more connected to the contralateral hemisphere than the left. Finally, sex and premature birth had effects on both STS volume and connectivity. Female neonates displayed a lesser left-right asymmetry in STS depth, and heightened connectivity from the left posterior STS compared to males. Most importantly, despite equivalent scan age, full-term newborns had deeper sulci compared with preterms, and local connectivity in the right temporal region increased linearly with gestation length. These results emphasize the impact of both sex and early auditory environment on the setting up of the cerebral networks that might contribute to explain the milder impact of premature birth on language in females. | | 6:16p |
Oligodendrocyte dependent synchronized activity orchestrates circuit maturation and brain functionalization
Immature animals have the ability to interact with their environment, indicating that complex neural circuits are formed through mechanisms of self-organization. Correlated spontaneous activity among neurons suggests a universal principle behind the self-organization of complex neural circuits1,2, though the underlying mechanisms and functional roles in the central nervous system remain unclear. Here, we show that oligodendrocyte-dependent synchronized spontaneous activity during the critical period is indispensable for neural circuit refinement and brain functionalization. We found that oligodendrocyte deletion during specific time window disrupts Purkinje cell activity synchrony and synapse elimination in the mouse cerebellum. We further demonstrated that synchronized spontaneous activity is a prerequisite for synapse elimination. Behavioral analyses linked these developmental disruptions to adult cerebellar function, manifesting as anxiety-like behavior, reduced social interaction, and compromised motor coordination in adult mice. This association indicates the significance of following the appropriate developmental trajectory to ensure the integrity of brain function, suggesting that oligodendrocytes during development are vital organizers of brain functionalization. Our findings highlight the crucial role of oligodendrocytes in orchestrating synapse elimination and optimizing brain function through the mediation of synchronized activity during specific developmental stages. | | 6:16p |
Remote automated delivery of mechanical stimuli coupled to brain recordings in behaving mice
The canonical framework for testing pain and mechanical sensitivity in rodents is manual delivery of stimuli to the paw. However, this approach can produce variability in results, requires significant training, and is ergonomically unfavorable to the experimenter. To circumvent limitations in manual delivery of stimuli, we have created a device called the ARM (Automated Reproducible Mechano-stimulator). Built using a series of linear stages, cameras, and stimulus holders, the ARM is more accurate at hitting the desired target, delivers stimuli faster, and decreases variability in delivery of von Frey hair filaments. We demonstrate that the ARM can be combined with traditional measurements of pain behavior and automated machine-learning based pipelines. Importantly, the ARM enables remote testing of mice with experimenters outside the testing room. Using remote testing, we found that mice appeared to habituate more quickly when an experimenter was not present and experimenter presence leads to significant sex-dependent differences in withdrawal behavior. Lastly, to demonstrate the utility of the ARM for neural circuit dissection of pain mechanisms, we combined the ARM with cellular-resolved microendoscopy in the amygdala, linking stimulus, behavior, and brain activity of amygdalar neurons that encode negative pain states. Taken together, the ARM improves speed, accuracy, and robustness of mechanical pain assays and can be combined with automated pain detection systems and brain recordings to map pain sensation and affect. | | 6:16p |
Chronic abolition of evoked vesicle release from layer 5 projection neurons disrupts the laminar distribution of parvalbumin interneurons in the adult cortex
Establishing precisely built neuronal networks during cortical development requires appropriate proportions of glutamatergic and GABAergic neurons. Developmental disturbances in pyramidal neuron activity can impede the development of GABAergic neurons with long-lasting effects on inhibitory networks. However, the role of deep-layer pyramidal neurons in instructing the development and distribution of GABAergic neurons remains unknown. To unravel the role of deep-layer pyramidal neuron activity in orchestrating the spatial and laminar organisation of parvalbumin neurons, we selectively manipulated the activity of projection neurons in layer 5 of the cortex. By ablating SNAP25 from subsets of glutamatergic L5 projection neurons across the cortical mantle, we abolished Ca2+-dependent vesicle release from Rbp4-Cre+ pyramidal neurons. We explored the local (location of the cell bodies) and the global (subcortical projection sites) effects of chronically silencing cortical L5 neurons on parvalbumin interneurons. We found that the chronic cessation of vesicle release from L5 projection neurons left the density, distribution, and developmental trajectory of cortical and subcortical PV neurons intact during the second and third postnatal week; however, it resulted in the reorganisation of the laminar distribution of cortical PV neurons in layer 4 of S1 in the adult cortex. The abolition of evoked vesicle release from L5 also affected the perineuronal nets in the adult motor cortex and revealed a significant decrease in the density of VVA+ and PV- VVA+ cells in L5 of M1 at 3 months of age. The alterations in the laminar arrangement of VVA+ neurons may imply that Ca2+-dependent synaptic transmission from L5 may control PNN density in adult networks. We also discovered that the absence of L5 activity only had a transient effect on the morphology of striatal PV neurons. The correlation between PV and VVA neurons was contingent on brain regions and cortical layers, therefore the link between the perineuronal net and PV neurons is significantly more intricate than previously believed. The present study will aid our understanding of the bidirectional relationship between deep-layer pyramidal cells and GABAergic neurons while uncovering the long-term effects of chronically disrupting pyramidal neurons on inhibitory networks. | | 6:47p |
Timing Matters: Lessons from Perinatal Neurogenesis in the Olfactory Bulb
In the olfactory bulb odorant receptor specific input converges into glomeruli. Deep to the glomeruli coding of odor information is tuned by local synaptic circuits. Deciphering the dendritic organization of granule cells relative to the secondary dendrites of projection neurons is a pivotal for understanding odor processing. We carried out a detailed interrogation of the granule cells including the timing of neurogenesis, laminar distribution and synaptogenesis between granule cells and projection neurons. In brief, the granule cells develop following a outside in maturation pattern from embryogenesis to adulthood following a developmental continuum. Granule cells born one week after birth exhibit a unique sublayer specific distribution pattern, marking a transition between embryonic or neonatal and adult stages. Integration into reciprocal synaptic circuits occurred 10 days post neurogenesis, We conclude that timing of neurogenesis dictates the anatomical configuration of granule cells within the olfactory bulb, which in turn regulates a preferential synaptic integration with either mitral cell or tufted cell secondary dendrites. | | 7:15p |
The visuomotor transformations underlying defensive behaviors and hunting
The visual system can identify stimuli as predators or prey, and respond with appropriate behaviors. To observe the transformation of visual information into behavior, we imaged the zebrafish visual system while larvae responded to three types of visual stimuli with innate hunting, freezing, and escape behaviors. We systematically identified visually driven neurons and behaviorally correlated sensorimotor neurons, and analyzed their responses to the different stimuli and behaviors. We found that the optic tectum contains broadly tuned sensory neurons, and sensorimotor neurons that respond specifically during one behavior. We also identified sensorimotor neurons in four other areas thought to be downstream of the tectum. Our findings support a model in which neurons in the tectum receive visual information describing an object's location, and may also receive input on the object's identity and the animal's state, in order to select a single behavioral outcome, which is then relayed to downstream areas. | | 8:00p |
Neuronal and oligodendroglial but not astroglial tau translates to in vivo tau-PET signals in primary tauopathies
Tau-PET receives growing interest as an imaging biomarker for the 4-repeat tauopathy progressive supranuclear palsy (PSP). However, the translation of in vitro 4R-tau binding to in vivo tau-PET signals is still unclear. Therefore, we conducted a longitudinal [18F]PI-2620 PET/MRI study in a 4-repeat-tau mouse model (PS19) and found elevated [18F]PI-2620 PET signal in the presence of high neuronal tau. Cell sorting after radiotracer injection in vivo revealed higher tracer uptake in single neurons compared to astrocytes of PS19 mice. Regional [18F]PI-2620 tau-PET signals during lifetime correlated with abundance of fibrillary tau in subsequent autopsy samples of PSP patients and disease controls. In autoradiography, tau-positive neurons and oligodendrocytes with high AT8 density but not tau-positive astrocytes were the driver of [18F]PI-2620 autoradiography signals in PSP. In summary, neuronal and oligodendroglial tau constitutes the dominant source of tau-PET radiotracer binding in 4-repeat-tauopathies, yielding the capacity to translate to an in vivo signal. |
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