eNeuro最新文献

The Bone Morphogenetic Protein (BMP) signaling pathway is vital in neural progenitor cell proliferation, specification, and differentiation. The BMP signaling antagonist Gremlin 2 (Grem2) is the most potent natural inhibitor of BMP expressed in the adult brain; however its function remains unknown. To address this knowledge gap, we have analyzed mice lacking Grem2 via homologous recombination (Grem2^-/- ). Histological analysis of brain sections revealed significant scattering of CA3 pyramidal cells within the dentate hilus in the hippocampus of Grem2^-/- mice. Furthermore, the number of proliferating neural stem cells and neuroblasts was significantly decreased in the subgranular zone of Grem2^-/- mice compared with that of wild-type (WT) controls. Due to the role of hippocampal neurogenesis in neurological disorders, we tested mice on a battery of neurobehavioral tests. Grem2^-/- mice exhibited increased anxiety on the elevated zero maze in response to acute and chronic stress. Specifically, male Grem2^-/- mice showed increased anxiogenesis following chronic stress, and this was correlated with higher levels of BMP signaling and decreased proliferation in the dentate gyrus. Additionally, when chemically challenged with kainic acid, Grem2^-/- mice displayed a higher susceptibility to and increased severity of seizures compared with WTs. Together, our data indicate that Grem2 regulates BMP signaling and is vital in maintaining homeostasis in adult hippocampal neurogenesis and structure. Furthermore, the lack of Grem2 contributes to the development and progression of neurogenesis-related disorders such as anxiety and epilepsy.

It is a common belief that memories, over time, become progressively independent of the hippocampus and are gradually stored in cortical areas. This view is mainly based on evidence showing that prefrontal cortex (PFC) manipulations impair the retrieval of remote memories, while hippocampal inhibition does not. More controversial is whether activity in the medial PFC is required immediately after learning to initiate consolidation. Another question concerns functional differences among PFC subregions in forming and storing remote memories. To address these issues, we directly contrasted the effects of loss-of-function manipulations of the anterior cingulate cortex (aCC) and the ventromedial PFC, which includes the infralimbic (IL) and prelimbic (PL) cortices, before testing and immediately after training on the ability of CD1 mice to recall the hidden platform location in the Morris water maze. We injected an AAV carrying the hM4Di receptor into the PL-IL or aCC. Interestingly, pretest administrations of clozapine-N-oxide (CNO; 3 mg/kg) revealed that the aCC, but not the PL-IL, was necessary to recall remote spatial information. Furthermore, systemic post-training administration of CNO impaired memory recall at remote, but not recent, time points in both groups. These findings revealed a functional dissociation between the two prefrontal areas, demonstrating that both the PL-IL and the aCC are involved in early consolidation of remote spatial memories, but only the aCC is engaged in their recall.

Two-photon calcium imaging allows for the activity readout of large populations of neurons at single cell resolution in living organisms, yielding new insights into how the brain processes information. Holographic optogenetics allows us to trigger activity of this population directly, raising the possibility of injecting information into a living brain. Optogenetic triggering of activity that mimics "natural" information, however, requires identification of stimulation targets based on real-time analysis of the functional network. We have developed NeuroART (Neuronal Analysis in Real Time), software that provides real-time readout of neuronal activity integrated with downstream analysis of correlations and synchrony and of sensory metadata. On the example of auditory stimuli, we demonstrate real-time inference of the contribution of each neuron in the field of view to sensory information processing. To avoid the limitations of microscope hardware and enable collaboration of multiple research groups, NeuroART taps into microscope data streams without the need for modification of microscope control software and is compatible with a wide range of microscope platforms. NeuroART also integrates the capability to drive a spatial light modulator (SLM) for holographic photostimulation of optimal stimulation targets, enabling real-time modification of functional networks. Neurons used for photostimulation experiments were extracted from Sprague Dawley rat embryos of both sexes.

Advances in single-cell technologies have led to the discovery and characterization of new brain cell types, which in turn lead to a better understanding of the pathogenesis of Alzheimer's disease (AD). Here, we present a detailed analysis of single-nucleus (sn)RNA-seq data for three stages of AD from middle temporal gyrus and compare it with snRNA-seq data from the prefrontal cortices from individuals with alcohol use disorder (AUD). We observed a significant decrease in both inhibitory and excitatory neurons, in general agreement with previous reports. We observed several cell-type-specific gene expressions and pathway dysregulations that delineate AD stages. Endothelial and vascular leptomeningeal cells showed the greatest degree of gene expression changes. Cell-type-specific evidence of neurodegeneration was seen in multiple neuronal cell types particularly in somatostatin and Layer 5 extratelencephalic neurons, among others. Evidence of inflammatory responses was seen in non-neuronal cells, particularly in intermediate and advanced AD. We observed common perturbations in AD and AUD, particularly in pathways, like transcription, translation, apoptosis, autophagy, calcium signaling, neuroinflammation, and phosphorylation, that imply shared transcriptional pathogenic mechanisms and support the role of excessive alcohol intake in AD progression. Major AUD gene markers form and perturb a network of genes significantly associated with intermediate and advanced AD. Master regulator analysis from AUD gene markers revealed significant correlation with advanced AD of transcription factors that have implications in intellectual disability, neuroinflammation, and other neurodegenerative conditions, further suggesting a shared nexus of transcriptional changes between AD and AUD.

Animals, humans included, navigate their environments guided by sensory cues, responding adaptively to potential dangers and rewards. Avoidance behaviors serve as adaptive strategies in the face of signaled threats, but the neural mechanisms orchestrating these behaviors remain elusive. Current circuit models of avoidance behaviors indicate that the nucleus accumbens (NAc) in the ventral striatum plays a key role in signaled avoidance behaviors, but the nature of this engagement is unclear. Evolving perspectives propose the NAc as a pivotal hub for action selection, integrating cognitive and affective information to heighten the efficiency of both appetitive and aversive motivated behaviors. To unravel the engagement of the NAc during active and passive avoidance, we used calcium imaging fiber photometry to examine NAc GABAergic neuron activity in ad libitum moving mice performing avoidance behaviors. We then probed the functional significance of NAc neurons using optogenetics and genetically targeted or electrolytic lesions. We found that NAc neurons code contraversive orienting movements and avoidance actions. However, direct optogenetic inhibition or lesions of NAc neurons did not impair active or passive avoidance behaviors, challenging the notion of their purported pivotal role in adaptive avoidance. The findings emphasize that while the NAc encodes avoidance movements, it is not required for avoidance behaviors, highlighting the distinction between behavior encoding or representation and mediation or generation.

Autonoetic consciousness (ANC), the ability to re-experience personal past events links episodic memory and self-consciousness by bridging awareness of oneself in a past event (i.e., during its encoding) with awareness of oneself in the present (i.e., during the reliving of a past event). Recent neuroscience research revealed a bodily form of self-consciousness, including the sense of agency (SoA) and the sense of body ownership (SoO) that are based on the integration of multisensory bodily inputs and motor signals. However, the relation between SoA and/or SoO with ANC is not known. Here, we used immersive virtual reality technology and motion tracking and investigated the potential association of SoA/SoO with ANC. For this, we exposed participants to different levels of visuomotor and perspectival congruency, known to modulate SoA and SoO, during the encoding of virtual scenes and collected ANC ratings 1 week after the encoding session. In a total of 74 healthy participants, we successfully induced systematic changes in SoA and SoO during encoding and found that ANC depended on the level of SoA experienced during encoding. Moreover, ANC was positively associated with SoA, but only for the scene encoded with preserved visuomotor and perspectival congruency, and such SoA-ANC coupling was absent for SoO and control questions. Collectively, these data provide behavioral evidence in a novel paradigm that links a key subjective component of bodily self-consciousness during encoding, SoA, to the subjective reliving of those encoded events from one's past, ANC.

Decision bias influences estimates of the absolute visual threshold. However, most psychophysical estimates of the murine absolute visual threshold have not taken bias into account. Here we developed a one-alternative forced choice (1AFC) assay to assess the decision bias of mice at the absolute visual threshold via the theory of signal detection and compared our approach with the more conventional high-threshold theoretic approach. In the 1AFC assay, mice of both sexes were trained to signal whether they detected a flash stimulus. We directly measured both hit and false alarm rates, which were used to estimate d' Using the theory of signal detection, we obtained absolute thresholds by interpolating the intensity where d' = 1 from d'-psychometric functions. This gave bias-independent estimates of the absolute visual threshold which ranged over sixfold, averaging ∼1 R* in 1,000 rods (n = 7 mice). To obtain high-threshold theoretic estimates of the absolute visual threshold from the same mice, we estimated threshold intensities from the frequency of seeing curves, corrected for guessing. This gave us thresholds that were strongly correlated with decision bias, ranging over 13-fold and averaged ∼1 R* in 2,500 rods. We conclude that the theory of signal detection uses false alarms to overcome decision bias and narrow the range of threshold estimates in mice, providing a powerful tool for understanding detection behavior near absolute visual threshold.

Alcohol use disorder (AUD) is a significant global health issue. Despite historically higher rates among men, AUD prevalence and negative alcohol-related outcomes in women are rising. Loneliness in humans has been associated with increased alcohol use, and traditional rodent drinking models involve single housing, presenting challenges for studying social enrichment. We developed LIQ PARTI (Lick Instance Quantifier with Poly-Animal RFID Tracking Integration), an open-source tool to examine home cage continuous access two-bottle choice drinking behavior in a group-housed setting, investigating the influence of sex and social isolation on ethanol consumption and bout microstructure in C57Bl/6J mice. LIQ PARTI, based on our previously developed single-housed LIQ HD system, accurately tracks drinking behavior using capacitive-based sensors and RFID technology. Group-housed female mice exhibited higher ethanol preference than males, while males displayed a unique undulating pattern of ethanol preference linked to cage changes, suggesting a potential stress or novelty-related response. Chronic ethanol intake distinctly altered bout microstructure between male and female mice, highlighting sex and social environmental influences on drinking behavior. Social isolation with the LIQ HD system amplified fluid intake and ethanol preference in both sexes, accompanied by sex- and fluid-dependent changes in bout microstructure. However, these effects largely reversed upon resocialization, indicating the plasticity of these behaviors in response to social context. Utilizing a novel group-housed home cage lickometer device, our findings illustrate the critical interplay of sex and housing conditions in voluntary alcohol drinking behaviors in C57Bl/6J mice, facilitating nuanced insights into the potential contributions to AUD etiology.