bioRxiv Subject Collection: Neuroscience's Journal
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Sunday, December 1st, 2024
| Time |
Event |
| 2:31a |
Neural evidence for action-related somatosensory predictions
The tactile consequences of self-initiated movements are thought to be predicted by a forward model, yet the precise neural implementation of these predictions remains unclear. In non- motor contexts, expectations are thought to activate sensory neurons tuned towards the expected stimulus. This acts as a predictive template against which afferent sensory input is compared. It is unclear whether forward model predictions have a similar neural instantiation. Here we employed time-resolved multivariate decoding on human electroencephalography (EEG) during self-generated movements to examine the content of predictive neural activity. Human participants performed index finger movements which were predictably paired with a vibration to either the index or ring finger of the opposite, passive hand. On some trials the tactile stimulus was unexpectedly omitted. Results revealed above-chance finger decoding in the pre-movement period supporting a predictive representation of expected stimulation location. As the movement approached, this predictive activity became similar to late-stage processing of a physical tactile stimulus. On omission trials, we found that despite the absence of afferent input, finger location could be decoded [~]120 ms after expected stimulus onset. This shows a stimulus-specific omission response. Together these findings indicate that self-generated movement pre-activates neurons tuned towards expected tactile consequences. | | 12:20p |
Sex-and Stress-Dependent Plasticity of a Corticotropin Releasing Hormone / GABA Projection from the Basolateral Amygdala to Nucleus Accumbens that Mediates Reward Behaviors
Background: Motivated behaviors are executed by refined brain circuits. Early-life adversity (ELA) is a risk for human affective disorders involving dysregulated reward behaviors. In mice, ELA causes anhedonia-like behaviors in males and augmented reward motivation in females, indicating sex-dependent disruption of reward circuit operations. We recently identified a corticotropin-releasing hormone (CRH) expressing GABAergic projection from basolateral amygdala (BLA) to nucleus accumbens (NAc) that governs reward-seeking deficits in adult ELA males, but not females. Methods: To probe the sex-specific role of this projection in reward behaviors, adult male and female CRH-Cre mice raised in control or ELA conditions received excitatory or inhibitory Cre-dependent DREADDs in BLA, and then clozapine N-oxide or vehicle to NAc medial shell during reward behaviors. We determined the cell identity of the projection using immunostaining and electrophysiology. Using tissue clearing, light sheet fluorescence microscopy and deep learning pipelines, we mapped brain-wide BLA CRH+ axonal projections to uncover sex differences in innervation. Results: Chemogenetic manipulations in male mice demonstrated inhibitory effects of the CRH+ BLA-NAc projection on reward behaviors, whereas neither excitation nor inhibition influenced female behaviors. Molecular and electrophysiological cell-identities of the projection did not vary by sex. By contrast, comprehensive whole-brain mapping uncovered significant differences in NAc innervation patterns that were both sex and ELA-dependent, as well as selective changes of innervation of other brain regions. Conclusions: The CRH/GABA BLA-NAc projection that influences reward behaviors in males differs structurally and functionally in females, uncovering potential mechanisms for the profound sex-specific impacts of ELA on reward behaviors. | | 9:47p |
Anorectic and anxiogenic actions of cocaine- and amphetamine-regulated transcript in the lateral septum
Cocaine- and amphetamine-regulated transcript (CART) is produced in several brain regions including the hypothalamus where it is made in cells that also produce melanin-concentrating hormone (MCH). MCH+CART cells densely innervate the lateral septum (LS), which integrates food- and mood-related behaviours. However, while MCH typically promotes feeding and anxiolysis, CART suppresses feeding and promotes anxiogenesis. The LS is a target site of the orexigenic actions of MCH, but it is not known if the actions of CART converge or oppose that of MCH in the LS. We implanted a bilateral cannula over the lateral or central LS of male and female wildtype mice and infused vehicle, CART55-102, or co-infused CART and MCH. CART did not alter chow intake but suppressed the intake of a palatable high sugar diet in male and female mice, especially when delivered in the medial LS. Furthermore, CART also prevented the orexigenic effect of MCH on palatable feeding intake when infused in the medial LS. We then assessed if CART regulated anxiety-like behaviour via the LS and found that intra-LS CART infusion reduced time spent in the center of an open field in male but not female mice. Our findings indicated that CART elicited anorectic and anxiogenic actions and may function in opposition to or independently of MCH in the LS. These outcomes suggested that putative CART and MCH co-release from MCH neurons may provide biphasic regulation of feeding and anxiety via the LS. | | 9:47p |
Individual uniqueness of connectivity gradients is driven by the complexity of the embedded networks and their dispersion
Connectivity gradients are widely used to characterize meaningful principles of functional brain organization in health and disease. However, the degree of individual uniqueness and shared common principles is not yet fully understood. Here, we leveraged the Hangzhou test-retest dataset, comprising repeated resting-state fMRI scans over the span of one month, to investigate the balance between individual variation and shared patterns of brain organization. We quantified the short- and long-term stability for the first three connectivity gradients and used connectome fingerprinting to establish the associated individual identification rate. We found that all three connectivity gradients are highly correlated over both short and long time intervals, demonstrating connectome fingerprinting utility. Individual uniqueness was dictated by the complexity of the networks such that heteromodal networks had higher connectome fingerprinting rates than unimodal networks. Importantly, the dispersion of the gradient coefficients associated with canonical functional networks was correlated with identification rates, irrespective of the position along the gradients. Beyond individual uniqueness, between subject similarity was high along the first connectivity gradient, which captures the dissociation between unimodal and heteromodal cortices, and the second connectivity gradient, which differentiates sensory cortices. Our results support the usage of connectivity gradients for the purposes of both group comparisons and prediction of individual behaviours. Our work adds to existing knowledge on the shared versus unique organizational principles and offers insights into the importance of network dispersion to the individual uniqueness it carries. | | 9:47p |
Robust characterization of selectivity of individual neurons to distinct task-relevant behavioral states using calcium imaging
Investigations into the neural basis of behavior have recently employed fluorescence imaging of calcium dynamics in a variety of brain areas to measure neural responses. However, across studies, diverse and seemingly subjective methodological choices have been made in assessing the selectivity of individual neurons to task-relevant behavioral states. Here, we examine systematically the effect of different choices in the values of key parameters from data acquisition through statistical testing on the inference of the selectivity of individual neurons for task states. We do so by using as an experimental testbed, neuronal calcium dynamics imaged in the medial prefrontal cortex of freely behaving mice engaged in a classic exploration-avoidance task involving spontaneous (animal-controlled) state transitions - navigation in the elevated zero maze (EZM). We report that a number of key variables in this pipeline substantially impact the selectivity label assigned to neurons, and do so in distinct ways. By quantitatively comparing newly defined accuracy and robustness metrics for all the 128 possible combinations of levels of the key parameters, we discover in a data-driven manner, two optimal combinations that reliably characterize neuronal selectivity - one using discrete calcium events and another using continuous calcium traces. This work establishes objective and standardized parameter settings for reliable, calcium imaging-based investigations into the neural encoding of task-states. | | 9:47p |
Internal states emerge early during learning of a perceptual decision-making task
Recent work has shown that during perceptual decision-making tasks, animals frequently alternate between different internal states or strategies. However, the question of how or when these emerge during learning remains an important open problem. Does an animal alternate between multiple strategies from the very start of training, or only after extensive exposure to a task? Here we address this question by developing a dynamic latent state model, which we applied to training data from mice learning to perform a visual decision-making task. Remarkably, we found that mice exhibited distinct "engaged" and "biased" states even during early training, with multiple states apparent from the second training session onward. Moreover, our model revealed that the gradual improvement in task performance over the course of training arose from a combination of two factors: (1) increased sensitivity to stimuli across all states; and (2) increased proportion of time spent in a higher-accuracy "engaged" state relative to biased or disengaged states. These findings highlight the power of our approach for characterizing the temporal evolution of multiple strategies across learning. | | 9:47p |
The ALS-associated co-chaperone DNAJC7 mediates neuroprotection against proteotoxic stress by modulating HSF1 activity
The degeneration of neurons in patients with amyotrophic lateral sclerosis (ALS) is commonly associated with accumulation of misfolded, insoluble proteins. Heat shock proteins (HSPs) are central regulators of protein homeostasis as they fold newly synthesized proteins and refold damaged proteins. Heterozygous loss-of-function mutations in the DNAJC7 gene that encodes an HSP co-chaperone were recently identified as a cause for rare forms of ALS, yet the mechanisms underlying pathogenesis remain unclear. Using mass spectrometry, we found that the DNAJC7 interactome in human motor neurons (MNs) is enriched for RNA binding proteins (RBPs) and stress response chaperones. MNs generated from iPSCs with the ALS-associated mutation R156X in DNAJC7 exhibit increased insolubility of its client RBP HNRNPU and associated RNA metabolism alterations. Additionally, DNAJC7 haploinsufficiency renders MNs increasingly susceptible to proteotoxic stress and cell death as a result of an ablated HSF1 stress response pathway. Critically, expression of HSF1 in mutant DNAJC7 MNs is sufficient to rescue their sensitivity to proteotoxic stress, while postmortem ALS patient cortical neurons exhibit a reduction in the expression of HSF1 pathway genes. Taken together, our work identifies DNAJC7 as a crucial mediator of HNRNPU function and stress response pathways in human MNs and highlights HSF1 as a therapeutic target in ALS. | | 9:47p |
A tool to automate assessment of regional brain atrophy in mouse models of neurodegenerative disease
As life expectancy rises, so too does the prevalence of neurodegenerative diseases. Neurodegeneration causes progressive regional brain atrophy, typically initiating prior to symptom onset. Researchers measure the impact of potential treatments on atrophy in mouse models to assess their effectiveness. This is important because treatments designed to combat neuropathology are more likely to modify the disease, per contra to symptom management. Magnetic resonance imaging, while accurate in measurement of brain region structure volumes, is prohibitively expensive. Conversely, stereological volume assessment, the process of estimating the volume of individual 3D brain regions from imaged 2D brain sections, is more commonly used. This involves manually tracing brain region(s) of interest in regularly spaced imaged cross-sections to determine their 2D area, followed by application of the Cavalieri principle to estimate the volume. The pertinent caveats of this approach are the labor-intensive manual tracing process, and potential inaccuracies that arise due to human variation. To overcome these challenges, we have created a Neuropathology Assessment Tool (NAT) to automate regional brain tracing and identification using artificial intelligence (AI) and concepts from topological data analysis. The NAT was validated by comparing manual and NAT analysis of striatal volume in Huntington disease model mice. The NAT detected striatal atrophy with higher efficiency, 93.8% agreement with manual measurements, and lower inter-group variability. The NAT will increase efficiency of preclinical neuropathology assessment, allowing for a greater number of experimental therapies to be tested and facilitating drug discovery intractable neurodegenerative diseases. | | 9:47p |
Hypocretin Receptor 1 Blockade Early in Abstinence Prevents Incubation of Cocaine Seeking and Normalizes Dopamine Transmission
Abstinence from cocaine use has been shown to elicit a progressive intensification or "incubation" of cocaine craving/seeking that is posited to contribute to the propensity for relapse. While the mechanisms underlying incubation of cocaine seeking remain elusive, considerable evidence suggests that abstinence from cocaine promotes mesolimbic dopamine adaptations that may contribute to exaggerated cocaine seeking. Consequently, preventing these dopamine adaptations may reduce incubation of cocaine seeking. In the present studies we first examined if incubation of cocaine seeking was associated with aberrant dopamine transmission in the nucleus accumbens after seven days of abstinence from intermittent access to cocaine. Given the extensive evidence that hypocretins/orexins regulate motivation for cocaine, we then examined to what extent hypocretin receptor 1 antagonism on the first day of abstinence prevented incubation of cocaine seeking and dopamine adaptations later in abstinence. Results indicated that abstinence from intermittent access to cocaine engendered robust incubation of cocaine seeking in both female and male rats. We also observed aberrant dopamine transmission only in rats that displayed incubation of cocaine seeking. Further, we showed that a single injection of the hypocretin receptor 1 antagonist, RTIOX-276, on the first day of abstinence prevented incubation of cocaine seeking and aberrant dopamine transmission. These findings suggest that hypocretin receptor 1 antagonism may serve as a viable therapeutic for reducing cocaine craving/seeking, thus reducing the likelihood for relapse. | | 9:47p |
MortX: A Domain Generalization Benchmark for Mouse Cortex Segmentation and Registration
Mesoscale understanding of human brain development is crucial for understanding neurodevelopmental disorders. By applying AI techniques to analyze high-resolution, multi-modal brain imaging datasets across postnatal ages, researchers can study cortical development at the granular level. We introduce MortX, a benchmark dataset of the developing mouse cortex that captures multiple postnatal stages with annotations for distinct anatomical and functional subregions and layers. MortX features high-resolution imaging data including bright-field and fluorescence-labeled neuronal markers. We developed a standardized cortical atlas of genetic markers and manually registered it to brain section images for ground-truth labeling. The dataset serves as a benchmark for domain generalization in neuroimaging, enabling both classical and deep learning models to be trained on source brains and tested on unseen targets. Our results demonstrate generalized model performance and structural invariance across ages. We open-source MortX as a community resource for mouse brain segmentation and registration, emphasizing domain adaptation. This dataset addresses key challenges in mouse brain imaging and advances machine learning models that will help unravel neurodevelopmental disorders. | | 9:47p |
Renovating the Barnes maze for mouse models of Dementia with STARR FIELD: A 4-day protocol that probes learning rate, retention and cognitive flexibility.
Land-based mazes that require spatial cues to identify the location of a hiding-place are a low-stress method to evaluate learning rate and memory retention in mice. One version, the Barnes maze, allows quantification of naturalistic exploratory behaviors not evident in water-based tasks. As the task relies on innate behaviors, it does not require overtraining, making it more feasible to examine early learning and non-memory executive functions that are characteristic of some non-amnestic dementias. However, because it is difficult to hide odor cues in the traditional version of the maze, learning rate during individual trials can be difficult to interpret. We designed and tested the use of 3D-printed escape shuttles that can be made in duplicate, as well as a docking tunnel that allows mice to self-exit the maze to improve reproducibility and limit experimenter influence. In combination with maze turning and escape tunnel caps, we show our shuttles mitigate the possibility of undesired cues. We then compare use of our 4-day protocol across several mouse models of cognitive impairment. We demonstrate an additional stage, the STARR protocol (Spatial Training and Rapid Reversal), to better challenge executive functions such as working memory and behavioral flexibility. We examine commonly used outcome measures across mice with and without access to spatial cues, as well as across mouse models of cognitive impairment to demonstrate the use of our 4-day protocol. Overall, this protocol provides detailed instructions to build and perform a robust spatial maze that can help expand the range of deficits identified. Our findings will aid in interpretation of traditional protocols, as well as provide an updated method to screen for both amnestic and non-amnestic cognitive changes. |
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