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Sunday, August 4th, 2024
| Time |
Event |
| 7:45a |
Integration of sensory and fear memories in the rat medial temporal lobe
Wong et al. (2019) used a sensory preconditioning protocol to examine how sensory and fear memories are integrated in the rat medial temporal lobe. In this protocol, rats integrate a sound-light (sensory) memory that forms in stage 1 with a light-shock (fear) memory that forms in stage 2 to generate fear responses (freezing) across test presentations of the sound in stage 3. Here, we advance this research by showing that: 1) how/when rats integrate the sound-light and light-shock memories (online in stage 2 or at test in stage 3) changes with the number of sound-light pairings in stage 1; and 2) regardless of how/when it occurs, the integration requires communication between two regions of the medial temporal lobe: the perirhinal cortex and basolateral amygdala complex. Thus, "event familiarity" determines how/when sensory and fear memories are integrated but not the circuitry by which the integration occurs: this remains the same. | | 7:45a |
Restoration of striatal neuroprotective pathways by kinase inhibitor treatment of Parkinsons linked-LRRK2 mutant mice
Parkinsons disease-associated, activating mutations in Leucine Rich Repeat Kinase 2 (LRRK2) block primary cilia formation in cholinergic and parvalbumin interneurons and astrocytes in the striatum, decreasing the production of GDNF and NRTN neuroprotective factors that normally support dopaminergic neuron viability. We show here that 3 month-dietary administration of the MLi-2 LRRK2 kinase inhibitor restores primary cilia and the Hedgehog-responsive production of neuroprotective GDNF and NRTN by these neurons; cilia are also restored on cholinergic neurons of the pedunculopontine nucleus. Importantly, we detect recovery of striatal dopaminergic processes and decreased stress-triggered Hedgehog signaling by nigral dopaminergic neurons. Thus, pathogenic LRRK2-driven cilia loss is reversible in post-mitotic neurons and astrocytes, which suggests that early administration of specific LRRK2 inhibitors may have significant therapeutic benefit for patients in the future.
One Sentence SummaryKinase inhibitor restores cilia, Hedgehog signaling, neuroprotective factors and dopamine processes in Parkinsons linked-LRRK2 mouse striatum | | 8:17a |
Acute stress causes sex-dependent changes to ventral subiculum synapses, circuitry, and anxiety-like behavior
Experiencing a single severe stressor is sufficient to drive sexually dimorphic psychiatric disease development. The ventral subiculum (vSUB) emerges as a site where stress may induce sexually dimorphic adaptations due to its sex-specific organization and pivotal role in stress integration. Using a 1-hr acute restraint stress model, we uncover that stress causes a net decrease in vSUB activity in females that is potent, long-lasting, and driven by adrenergic receptor signaling. By contrast, males exhibit a net increase in vSUB activity that is transient and driven by corticosterone signaling. We further identified sex-dependent changes in vSUB output to the bed nucleus of the stria terminalis and in anxiety-like behavior in response to stress. These findings reveal striking changes in psychiatric disease-relevant brain regions and behavior following stress with sex-, cell-type, and synapse-specificity that contribute to our understanding of sex-dependent adaptations that may shape stress-related psychiatric disease risk.
HighlightsO_LIvSUB BS cells are uniquely stress sensitive
C_LIO_LIStress causes sex-dependent changes to BS cell E/I balance
C_LIO_LIStress causes sex-dependent changes to vSUB activity to aBNST in vivo
C_LIO_LIStress causes anxiety-like behavior in females, but not males
C_LI | | 8:17a |
Biophysical Simulation Enables Multi-Scale Segmentation and Atlas Mapping for Top-Down Spatial Omics of the Nervous System
Spatial omics (SO) has produced high-definition mappings of subcellular molecules (like transcripts or proteins) within various tissue samples. Most applications of SO are molecule-driven i.e. the spatial distributions of transcripts are used to make distinctions between samples. However, such inferences do not automatically utilize brain atlas regions. Here, we present SiDoLa-NS (Simulate, Dont Label - Nervous System), an image-driven (top-down) approach to SO analysis in the nervous system. We utilize the biophysical properties of tissue architectures to design synthetic images mimicking tissue samples. With these in silico samples, we train supervised instance segmentation models for nucleus segmentation, achieving near perfect precision and F1-scores > 0.95. We take this a step further with generalizable models that can identify macroscopic tissue structures in the mouse brain (mAP50 = 0.869) and spinal cord (mAP50 = 0.96) and pig sciatic nerve (mAP50 = 0.995). SiDoLa-NS provides a framework in applying and analyzing SO data that leverages high-definition images that are taken alongside spatial omics pipelines. Notably, SiDoLa-NS provides solutions for common challenges in supervised model training, including but not limited to annotator bias, limited generalizability, and production of massive, high-quality training sets.
Short SummaryThe SiDoLa-NS micro-, meso-, and macro-scale models are generalizable, supervised models for neuronal segmentation in cell to tissue-level contexts. SiDoLa-NS is novel in its combination of three core ideas: it is top-down (image first), trained solely on synthetic images, and it is multi-scale. The tool is validated on brain, spinal cord, and sciatic nerve for advanced segmentation tasks. | | 9:31a |
Bezafibrate treatment rescues neurodevelopmental and neurodegenerative defects in 3D cortical organoid model of MAPT frontotemporal dementia
INTRODUCTIONThe intronic MAPT mutation IVS10+16 is linked to familiar frontotemporal dementia, causing hyperphosphorylation and accumulation of tau protein, resulting in synaptic and neuronal loss and neuroinflammation in patients. This mutation disrupts MAPT gene splicing, increasing exon 10 inclusion and leading to an imbalance of 3R and 4R Tau isoforms.
METHODSWe generated patterned cortical organoids from isogenic control and mutant human iPSC lines. Nanostring gene expression analysis immunofluorescence and calcium imaging recordings were used to study the impact of the MAPT IVS10+16 mutation on neuronal development and function.
RESULTSTau mutant cortical organoids showed altered mitochondrial function and gene expression related to neuronal development, with synaptic markers and neuronal activity reduction. Bezafibrate treatment, which restored mitochondrial content, rescued synaptic functionality and tau physiology.
DISCUSSIONThese findings suggest that targeting mitochondrial function with bezafibrate could potentially reverse tau-induced neurodevelopmental deficits, highlighting its therapeutic potential for tauopathies like FTD.
HIGLIGHTSO_LIThe IVS 10+16 MAPT mutation significantly disrupts cortical differentiation and synaptic maturation, evidenced by downregulated genes associated with synapses and neuronal development.
C_LIO_LITau-mutant cortical organoids exhibit mitochondrial dysfunction, with fewer and smaller mitochondria alongside with tau hyperphosphorylation and aggregation, which further contribute to neuronal damage and disease progression.
C_LIO_LITreatment with bezafibrate effectively normalizes mitochondrial parameters, enhances neuronal integrity and synaptic maturation, and restores network functionality, showcasing its promise as a therapeutic strategy for tauopathies.
C_LIO_LIThe 3D in vitro disease model used in this study proves valuable for studying tauopathies and testing new drugs, effectively mimicking key aspects of tau-related neurodegeneration.
C_LI
RESEARCH IN CONTEXTO_LISystematic Review: We searched PubMed, Google Scholar, and Web of Science for studies on the MAPT IVS10+16 mutations impact on tauopathies, focusing on neuronal development, synaptic function, and mitochondrial involvement. Key terms included "MAPT IVS10+16 mutation," "tauopathy," "neuronal development," "synaptic function," and "mitochondrial function."
C_LIO_LIInterpretation: Our findings reveal that the MAPT IVS10+16 mutation disrupts mitochondrial function altering gene expression related to neuronal development, synaptic structures, impairing neuronal and glial maturation. Bezafibrate treatment restored mitochondrial content, synaptic functionality, and tau physiology in mutant-derived cortical organoids, suggesting it as a potential therapeutic strategy for tauopathies.
C_LIO_LIFuture Directions: Future research should investigate the molecular mechanisms underlying the bezafibrates therapeutic effect and its long-term efficacy and safety in vivo, in humanized mouse models. Additionally, the possibility to combine bezafibrate with other therapeutic agents used to treat tauopathies will be worth to assess.
C_LI | | 9:31a |
Humans use local spectrotemporal correlations to detect rising and falling pitch
To discern speech or appreciate music, the human auditory system detects how pitch increases or decreases over time. However, the algorithms used to detect changes in pitch, or pitch motion, are incompletely understood. Here, using psychophysics, computational modeling, functional neuroimaging, and analysis of recorded speech, we ask if humans detect pitch motion using computations analogous to those used by the visual system. We adapted stimuli from studies of vision to create novel auditory correlated noise stimuli that elicited robust pitch motion percepts. Crucially, these stimuli possess no persistent features across frequency or time, but do possess positive or negative local spectrotemporal correlations in intensity. In psychophysical experiments, we found clear evidence that humans judge pitch direction based on both positive and negative spectrotemporal correlations. The observed sensitivity to negative correlations is a direct analogue of illusory "reverse-phi" motion in vision, and thus constitutes a new auditory illusion. Our behavioral results and computational modeling led us to hypothesize that human auditory processing employs pitch direction opponency. fMRI measurements in auditory cortex supported this hypothesis. To link our psychophysical findings to real-world pitch perception, we analyzed recordings of English and Mandarin speech and discovered that pitch direction was robustly signaled by the same positive and negative spectrotemporal correlations used in our psychophysical tests, suggesting that sensitivity to both positive and negative correlations confers ecological benefits. Overall, this work reveals that motion detection algorithms sensitive to local correlations are deployed by the central nervous system across disparate modalities (vision and audition) and dimensions (space and frequency). | | 9:31a |
Concerted modulation of spontaneous behavior and time-integrated whole-brain neuronal activity by serotonin receptors
Serotonin neurons from the raphe nuclei project across the entire brain and modulate diverse physiology and behavior by acting on 14 distinct receptors. Here, we take a step dissecting this complex process by examining the effects of agonists and antagonists of four widely expressed serotonin receptors (2A, 2C, 1A, and 1B) on spontaneous mouse behavior. We also analyzed time-integrated whole-brain neuronal activity of these same mice based on intensity of Fos, product of an immediate-early gene. Low-dimensional representations of behavioral and Fos map data shed light on the dominant factors of variation in each domain, captured predictable differences across drug groups, and enabled predictions of behavioral changes following perturbations in Fos maps and vice versa. Our study provides rich resources on the effects of manipulating serotonin receptors on animal behavior and whole-brain integrated neuronal activity. It also establishes an experimental and analysis paradigm for interrogating the relationship between behavior and neuronal activity across different time scales. | | 9:31a |
A general principle governing neuronal evolution reveals a human-accelerated neuron type potentially underlying the high prevalence of autism in humans
The remarkable ability of a single genome sequence to encode a diverse collection of distinct cell types, including the thousands of cell types found in the mammalian brain, is a key characteristic of multicellular life. While it has been observed that some cell types are far more evolutionarily conserved than others, the factors driving these differences in evolutionary rate remain unknown. Here, we hypothesized that highly abundant neuronal cell types may be under greater selective constraint than rarer neuronal types, leading to variation in their rates of evolution. To test this, we leveraged recently published cross-species single-nucleus RNA-sequencing datasets from three distinct regions of the mammalian neocortex. We found a strikingly consistent relationship where more abundant neuronal subtypes show greater gene expression conservation between species, which replicated across three independent datasets covering >106 neurons from six species. Based on this principle, we discovered that the most abundant type of neocortical neurons--layer 2/3 intratelencephalic excitatory neurons--has evolved exceptionally quickly in the human lineage compared to other apes. Surprisingly, this accelerated evolution was accompanied by the dramatic down-regulation of autism-associated genes, which was likely driven by polygenic positive selection specific to the human lineage. In sum, we introduce a general principle governing neuronal evolution and suggest that the exceptionally high prevalence of autism in humans may be a direct result of natural selection for lower expression of a suite of genes that conferred a fitness benefit to our ancestors while also rendering an abundant class of neurons more sensitive to perturbation. | | 9:31a |
The estrous cycle modulates hippocampal spine dynamics, dendritic processing, and spatial coding
AbstractHistological evidence suggests that the estrous cycle exerts a powerful effect on CA1 neurons in mammalian hippocampus. Decades have passed since this landmark observation, yet how the estrous cycle shapes dendritic spine dynamics and hippocampal spatial coding in vivo remains a mystery. Here, we used a custom hippocampal microperiscope and two-photon calcium imaging to track CA1 pyramidal neurons in female mice over multiple cycles. Estrous cycle stage had a potent effect on spine dynamics, with heightened density during periods of greater estradiol (proestrus). These morphological changes were accompanied by greater somatodendritic coupling and increased infiltration of back-propagating action potentials into the apical dendrite. Finally, tracking CA1 response properties during navigation revealed enhanced place field stability during proestrus, evident at the single-cell and population level. These results establish the estrous cycle as a driver of large-scale structural and functional plasticity in hippocampal circuits essential for learning and memory. |
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