Whole-Brain Reconstruction of Neurons in the Ventral Pallidum Reveals Diverse Projection Patterns

The ventral pallidum (VP) integrates reward signals to regulate cognitive, emotional, and motor processes associated with motivational salience. Previous studies have revealed that the VP projects axons to many cortical and subcortical structures. However, descriptions of the neuronal morphologies and projection patterns of the VP neurons at the single neuron level are lacking, thus hindering the understanding of the wiring diagram of the VP. In this study, we used recently developed progress in robust sparse labeling and fluorescence micro-optical sectioning tomography imaging system (fMOST) to label mediodorsal thalamus-projecting neurons in the VP and obtain high-resolution whole-brain imaging data. Based on these data, we reconstructed VP neurons and classified them into three types according to their fiber projection patterns. We systematically compared the axonal density in various downstream centers and analyzed the soma distribution and dendritic morphologies of the various subtypes at the single neuron level. Our study thus provides a detailed characterization of the morphological features of VP neurons, laying a foundation for exploring the neural circuit organization underlying the important behavioral functions of VP.

Air Pollution Particulate Matter Amplifies White Matter Vascular Pathology and Demyelination Caused by Hypoperfusion

Cerebrovascular pathologies are commonly associated with dementia. Because air pollution increases arterial disease in humans and rodent models, we hypothesized that air pollution would also contribute to brain vascular dysfunction. We examined the effects of exposing mice to nanoparticulate matter (nPM; aerodynamic diameter ≤200 nm) from urban traffic and interactions with cerebral hypoperfusion. C57BL/6 mice were exposed to filtered air or nPM with and without bilateral carotid artery stenosis (BCAS) and analyzed by multiparametric MRI and histochemistry. Exposure to nPM alone did not alter regional cerebral blood flow (CBF) or blood brain barrier (BBB) integrity. However, nPM worsened the white matter hypoperfusion (decreased CBF on DSC-MRI) and exacerbated the BBB permeability (extravascular IgG deposits) resulting from BCAS. White matter MRI diffusion metrics were abnormal in mice subjected to cerebral hypoperfusion and worsened by combined nPM+BCAS. Axonal density was reduced equally in the BCAS cohorts regardless of nPM status, whereas nPM exposure caused demyelination in the white matter with or without cerebral hypoperfusion. In summary, air pollution nPM exacerbates cerebrovascular pathology and demyelination in the setting of cerebral hypoperfusion, suggesting that air pollution exposure can augment underlying cerebrovascular contributions to cognitive loss and dementia in susceptible elderly populations.

Behavioral and Histopathological Impairments Caused by Topical Exposure of the Rat Brain to Mild-Impulse Laser-Induced Shock Waves: Impulse Dependency

Although an enormous number of animal studies on blast-induced traumatic brain injury (bTBI) have been conducted, there still remain many uncertain issues in its neuropathology and mechanisms. This is partially due to the complex and hence difficult experimental environment settings, e.g., to minimize the effects of blast winds (tertiary mechanism) and to separate the effects of brain exposure and torso exposure. Since a laser-induced shock wave (LISW) is free from dynamic pressure and its energy is spatially well confined, the effects of pure shock wave exposure (primary mechanism) solely on the brain can be examined by using an LISW. In this study, we applied a set of four LISWs in the impulse range of 15–71 Pa·s to the rat brain through the intact scalp and skull; the interval between each exposure was ~5 s. For the rats, we conducted locomotor activity, elevated plus maze and forced swimming tests. Axonal injury in the brain was also examined by histological analysis using Bodian silver staining. Only the rats with exposure at higher impulses of 54 and 71 Pa·s showed significantly lower spontaneous movements at 1 and 2 days post-exposure by the locomotor activity test, but after 3 days post-exposure, they had recovered. At 7 days post-exposure, however, these rats (54 and 71 Pa·s) showed significantly higher levels of anxiety-related and depression-like behaviors by the elevated plus maze test and forced swimming test, respectively. To the best of the authors' knowledge, there have been few studies in which a rat model showed both anxiety-related and depression-like behaviors caused by blast or shock wave exposure. At that time point (7 days post-exposure), histological analysis showed significant decreases in axonal density in the cingulum bundle and corpus callosum in impulse-dependent manners; axons in the cingulum bundle were found to be more affected by a shock wave. Correlation analysis showed a statistically significant correlation between the depression like-behavior and axonal density reduction in the cingulum bundle. The results demonstrated the dependence of behavior deficits and axonal injury on the shock wave impulse loaded on the brain.

Multi-tract multi-symptom relationships in pediatric concussions

The heterogeneity of white matter damage and symptoms in concussions has been identified as a major obstacle to therapeutic innovation. In contrast, the vast majority of diffusion MRI studies on concussion have traditionally employed group-comparison approaches. Such studies do not consider heterogeneity of damage and symptoms in concussion. To parse concussion heterogeneity, the present study combines diffusion MRI (dMRI) and multivariate statistics to investigate multi-tract multi-symptom relationships. Using dMRI data from a sample of 306 children ages 9 and 10 with a history of concussion from the Adolescent Brain Cognitive Development Study (ABCD study), we built connectomes weighted by classical and emerging diffusion measures. These measures were combined into two informative indices, the first capturing a mixture of patterns suggestive of microstructural complexity, the second representing almost exclusively axonal density. We deployed pattern-learning algorithms to jointly decompose these connectivity features and 19 behavioural measures that capture well-known symptoms of concussions. We found idiosyncratic symptom-specific multi-tract connectivity features, which would not be captured in traditional univariate analyses. Multivariable connectome-symptom correspondences were stronger than all single-tract/single-symptom associations. Multi-tract connectivity features were also expressed equally across different sociodemographic strata and their expression was not accounted for by injury-related variables. In a replication dataset, the expression of multi-tract connectivity features predicted adverse psychiatric outcomes after accounting for other psychopathology-related variables. By defining cross-demographic multi-tract multi-symptom relationships to parse concussion heterogeneity, the present study can pave the way for the development of improved stratification strategies that may contribute to the success of future clinical trials and the improvement of concussion management.

Microchannel patterning strategies for in vitro structural connectivity modulation of neural networks

Compartmentalized microfluidic chips have demonstrated tremendous potential to create in vitro minimalistic environments for the reproduction of the neural circuitry of the brain. Although the protocol for seeding neural soma in these devices is well known and has been widely used in myriad studies, the accurate control of the number of neurites passing through the microchannels remains challenging. However, the regulation of axonal density among different groups of neurons is still a requirement to assess the inherent structural connectivity between neuronal populations. In this work, we report the effect of microchannel patterning strategies on the modulation of neuronal connectivity by applying dimensional modifications on microchannel-connected microfluidic chambers. Our results show that those strategies can modulate the direction and the number of neuronal projections of passage, therefore regulating the strength of the structural connections between two populations of neurons. With this approach, we provide innovative microfluidic design rules for the engineering of in vitro physiologically relevant neural networks.