Vitamin D Enhances Hematoma Clearance and Neurologic Recovery in Intracerebral Hemorrhage.

BACKGROUND: Erythrophagocytosis by reparative monocyte-derived macrophage contributes to hematoma clearance and neurological recovery after intracerebral hemorrhage (ICH). Vitamin D (VitD) is a neuroprotective hormone and regulates the differentiation of monocyte-derived macrophage from monocytes. In this study, we examined the effects of VitD supplementation on monocyte-derived macrophage and hematoma clearance in rodent with ICH. METHODS: Neurobehavioral functions and hematoma volume were assessed using a collagenase injection model in both young- and middle-aged mice with or without VitD treatment given 2 hours post-ICH induction. We used flow cytometry to analyze CD36 expression and macrophage and undifferentiated monocyte cell numbers during in vivo erythrophagocytosis in collagenase and autologous blood injection models. Western blot analysis and immunofluorescence were used to assess the expression levels of the PPAR-γ (peroxisome proliferator-activated receptor γ)-CD36 axis and CD206. A macrophage differentiation study was conducted on murine bone marrow-derived monocytes. RESULTS: VitD promoted neurological recovery and facilitated hematoma clearance in both young- and middle-aged mice after ICH. Within the perihematomal region, mature macrophages, rather than undifferentiated monocytes, expressed higher levels of CD36 in driving erythrocyte clearance. VitD increased the macrophage number but decreased the monocyte number and elevated the levels of CD36 and PPAR-γ in the brain. In vitro, VitD accelerated the differentiation of reparative macrophages from bone marrow-derived monocytes. CONCLUSIONS: VitD promotes reparative macrophage differentiation, facilitates hematoma clearance, and improves neurobehavioral performance in mice with ICH, suggesting that VitD should be further examined as a potentially promising treatment for ICH.

Neural activity temporal pattern dictates long-range propagation targets.

Brain possesses a complex spatiotemporal architecture for efficient information processing and computing. However, it remains unknown how neural signal propagates to its intended targets brain-wide. Using optogenetics and functional MRI, we arbitrarily initiated various discrete neural activity pulse trains with different temporal patterns and revealed their distinct long-range propagation targets within the well-defined, topographically organized somatosensory thalamo-cortical circuit. We further observed that such neural activity propagation over long range could modulate brain-wide sensory functions. Electrophysiological analysis indicated that distinct propagation pathways arose from system level neural adaptation and facilitation in response to the neural activity temporal characteristics. Together, our findings provide fundamental insights into the long-range information transfer and processing. They directly support that temporal coding underpins the whole brain functional architecture in presence of the vast and relatively static anatomical architecture.

Early Detection of Amyloid ß Pathology in Alzheimer's Disease by Molecular MRI.

Alzheimer's disease (AD) is a degenerative brain disease and the most common cause of dementia. Early stage ß-amyloid oligomers (AßOs) and late stage Aß plaques are the pathological hallmarks of AD brains. AßOs are known to be more neurotoxic and contribute to neuronal damage. Most current approaches are focused on detecting Aß plaques, which occurs at the late stage of AD, and are limited by poor sensitivity and/or contrast agent toxicity. In previous studies, we developed a new curcumin-conjugated magnetic nanoparticle (Cur-MNPs) to target the Aß pathologies. In this study, we investigate the in vivo feasibility of this novel Cur-MNPs to detect Aß pathologies at the early and late stages of AD in transgenic AD mice and perform immunohistochemical examinations to validate the specific targeting of various form of Aß pathologies.

Altered d-glucose in brain parenchyma and cerebrospinal fluid of early Alzheimer's disease detected by dynamic glucose-enhanced MRI.

Altered cerebral glucose uptake is one of the hallmarks of Alzheimer's disease (AD). A dynamic glucose-enhanced (DGE) magnetic resonance imaging (MRI) approach was developed to simultaneously monitor d-glucose uptake and clearance in both brain parenchyma and cerebrospinal fluid (CSF). We observed substantially higher uptake in parenchyma of young (6 months) transgenic AD mice compared to age-matched wild-type (WT) mice. Notably lower uptakes were observed in parenchyma and CSF of old (16 months) AD mice. Both young and old AD mice had an obviously slower CSF clearance than age-matched WT mice. This resembles recent reports of the hampered CSF clearance that leads to protein accumulation in the brain. These findings suggest that DGE MRI can identify altered glucose uptake and clearance in young AD mice upon the emergence of amyloid plaques. DGE MRI of brain parenchyma and CSF has potential for early AD stratification, especially at 3T clinical field strength MRI.

Optogenetic fMRI interrogation of brain-wide central vestibular pathways.

Blood oxygen level-dependent functional MRI (fMRI) constitutes a powerful neuroimaging technology to map brain-wide functions in response to specific sensory or cognitive tasks. However, fMRI mapping of the vestibular system, which is pivotal for our sense of balance, poses significant challenges. Physical constraints limit a subject's ability to perform motion- and balance-related tasks inside the scanner, and current stimulation techniques within the scanner are nonspecific to delineate complex vestibular nucleus (VN) pathways. Using fMRI, we examined brain-wide neural activity patterns elicited by optogenetically stimulating excitatory neurons of a major vestibular nucleus, the ipsilateral medial VN (MVN). We demonstrated robust optogenetically evoked fMRI activations bilaterally at sensorimotor cortices and their associated thalamic nuclei (auditory, visual, somatosensory, and motor), high-order cortices (cingulate, retrosplenial, temporal association, and parietal), and hippocampal formations (dentate gyrus, entorhinal cortex, and subiculum). We then examined the modulatory effects of the vestibular system on sensory processing using auditory and visual stimulation in combination with optogenetic excitation of the MVN. We found enhanced responses to sound in the auditory cortex, thalamus, and inferior colliculus ipsilateral to the stimulated MVN. In the visual pathway, we observed enhanced responses to visual stimuli in the ipsilateral visual cortex, thalamus, and contralateral superior colliculus. Taken together, our imaging findings reveal multiple brain-wide central vestibular pathways. We demonstrate large-scale modulatory effects of the vestibular system on sensory processing.

Ginsenoside Rg1 Prevents Chemotherapy-Induced Cognitive Impairment: Associations with Microglia-Mediated Cytokines, Neuroinflammation, and Neuroplasticity.

Chemotherapy-induced cognitive impairment, also known as "chemobrain," is a common side effect. The purpose of this study was to examine whether ginsenoside Rg1, a ginseng-derived compound, could prevent chemobrain and its underlying mechanisms. A mouse model of chemobrain was developed with three injections of docetaxel, adriamycin, and cyclophosphamide (DAC) in combination at a 2-day interval. Rg1 (5 and 10 mg/kg daily) was given 1 week prior to DAC regimen for 3 weeks. An amount of 10 mg/kg Rg1 significantly improved chemobrain-like behavior in water maze test. In vivo neuroimaging revealed that Rg1 co-treatment reversed DAC-induced decreases in prefrontal and hippocampal neuronal activity and ameliorated cortical neuronal dendritic spine elimination. It normalized DAC-caused abnormalities in the expression of multiple neuroplasticity biomarkers in the two brain regions. Rg1 suppressed DAC-induced elevation of the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), but increased levels of the anti-inflammatory cytokines IL-4 and IL-10 in multiple sera and brain tissues. Rg1 also modulated cytokine mediators and inhibited DAC-induced microglial polarization from M2 to M1 phenotypes. In in vitro experiments, while impaired viability of PC12 neuroblastic cells and hyperactivation of BV-2 microglial cells, a model of neuroinflammation, were observed in the presence of DAC, Rg1 co-treatment strikingly reduced DAC's neurotoxic effects and neuroinflammatory response. These results indicate that Rg1 exerts its anti-chemobrain effect in an association with the inhibition of neuroinflammation by modulating microglia-mediated cytokines and the related upstream mediators, protecting neuronal activity and promoting neuroplasticity in particular brain regions associated with cognition processing.

Chemotherapy-Induced Cognitive Impairment Is Associated with Cytokine Dysregulation and Disruptions in Neuroplasticity.

Chemotherapy-induced cognitive impairment, often referred to as "chemobrain," is a common side effect. In this study, mice received three intraperitoneal injections of a combination of docetaxel, adriamycin, and cyclophosphamide (DAC) at 2-day intervals. A water maze test was used to examine cognitive performance, and manganese-enhanced magnetic resonance imaging (MEMRI) was used to examine hippocampal neuronal activity. The whole brain, prefrontal cortex, hippocampus, and blood samples were then collected for cytokine measurement. The DAC-treated mice displayed a significantly shorter duration spent in and fewer entries into the target quadrant of the water maze than the control mice and a pronounced decrease in MEMRI signal intensity in the hippocampal subregions. In a separate experiment using in vivo transcranial two-photon imaging, DAC markedly eliminated dendritic spines without changing the rate of spine formation, leading to a striking loss of spines in the medial prefrontal cortex. DAC treatment resulted in significant elevations in the levels of the proinflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) and in significant decreases in the levels of the anti-inflammatory cytokines IL-4 and IL-10 in most of the sera and brain tissues examined. The IL-6 and TNF-α levels of several sera and brain tissues showed strong inverse correlations with the duration and number of entries in the target quadrant of the water maze and with the hippocampal MEMRI signal intensity, but also showed striking positive correlations with spine elimination and loss. These results indicate that chemobrain is associated with cytokine dysregulation and disrupted neuroplasticity of the brain.

Functional MRI Investigation of Audiovisual Interactions in Auditory Midbrain.

The brain integrates information from different sensory modalities to form a representation of the environment and facilitate behavioral responses. The auditory midbrain or inferior colliculus (IC) is a pivotal station in the auditory system, integrating ascending and descending information from various auditory sources and cortical systems. The present study investigated the modulation of auditory responses in the IC by visual stimuli of different frequencies and intensities in rats using functional MRI (fMRI). Low-frequency (1 Hz) high-intensity visual stimulus suppressed IC auditory responses. However, high-frequency (10 Hz) or low-intensity visual stimuli did not alter the IC auditory responses. This finding demonstrates that cross-modal processing occurs in the IC in a manner that depends on the stimulus. Furthermore, only low-frequency high-intensity visual stimulus elicited responses in non-visual cortical regions, suggesting that the above cross-modal modulation effect may arise from top-down cortical feedback. These fMRI results provide insight to guide future studies of cross-modal processing in sensory pathways.

Auditory-visual convergence at the superior colliculus in rat using functional MRI.

The superior colliculus (SC) of the midbrain has been a model structure for multisensory processing. Many neurons in the intermediate and deep SC layers respond to two or more of auditory, visual, and somatosensory stimuli as assessed by electrophysiology. In contrast, noninvasive and large field of view functional magnetic resonance imaging (fMRI) studies have focused on multisensory processing in the cortex. In this study, we applied blood oxygenation leveldependent (BOLD) fMRI on Sprague-Dawley rats receiving monaural (auditory) and binocular (visual) stimuli to study subcortical multisensory processing. Activation was observed in the left superior olivary complex, lateral lemniscus, and inferior colliculus and both hemispheres of the superior colliculus during auditory stimulation. The SC response was bilateral even though the stimulus was monaural. During visual stimulation, activation was observed in both hemispheres of the SC and lateral geniculate nucleus. In both hemispheres of the SC, the number of voxels in the activation area $( \mathrm {p}<10 -8$) and BOLD signal changes $( \mathrm {p}<0.01)$ were significantly greater during visual than auditory stimulation. These results provide functional imaging evidence that the SC is a site of auditoryvisual convergence due to its involvement in both auditory and visual processing. The auditory and visual fMRI activations likely reflect the firing of unisensory and multisensory neurons in the SC. The present study lays the groundwork for noninvasive functional imaging studies of multisensory convergence and integration in the SC.

Optogenetic auditory fMRI reveals the effects of visual cortical inputs on auditory midbrain response.

Sensory cortices contain extensive descending (corticofugal) pathways, yet their impact on brainstem processing - particularly across sensory systems - remains poorly understood. In the auditory system, the inferior colliculus (IC) in the midbrain receives cross-modal inputs from the visual cortex (VC). However, the influences from VC on auditory midbrain processing are unclear. To investigate whether and how visual cortical inputs affect IC auditory responses, the present study combines auditory blood-oxygenation-level-dependent (BOLD) functional MRI (fMRI) with cell-type specific optogenetic manipulation of visual cortex. The results show that predominant optogenetic excitation of the excitatory pyramidal neurons in the infragranular layers of the primary VC enhances the noise-evoked BOLD fMRI responses within the IC. This finding reveals that inputs from VC influence and facilitate basic sound processing in the auditory midbrain. Such combined optogenetic and auditory fMRI approach can shed light on the large-scale modulatory effects of corticofugal pathways and guide detailed electrophysiological studies in the future.

Resveratrol, a natural polyphenol, prevents chemotherapy-induced cognitive impairment: Involvement of cytokine modulation and neuroprotection.

Chemotherapy-induced cognitive impairment, also known as "chemobrain," is a common side effect. The purpose of this study was to examine whether resveratrol, a natural polyphenol that has nootropic effects, could prevent chemobrain and its underlying mechanisms. Mice received three injections of docetaxel, adriamycin, and cyclophosphamide (DAC) in combination, a common chemotherapy regimen, at two-day intervals within one week. Resveratrol (50 and 100 mg/kg per day) was orally administered for three weeks, beginning one week before the DAC treatment. Water maze test and manganese-enhanced magnetic resonance imaging were used to evaluate animals' cognitive performance and brain neuronal activity, respectively. Blood and brain tissues were collected for measurement of cytokines, cytokine regulators, and biomarkers for neuroplasticity. DAC treatment produced a striking cognitive impairment. Cotreatment with 100 mg/kg resveratrol ameliorated DAC-induced cognitive impairment and decreases in prefrontal and hippocampal neuronal activity. Mice co-treated with both doses of resveratrol displayed significantly lower levels of the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), but markedly higher levels of the anti-inflammatory cytokines IL-4 and IL-10 in several sera and brain tissues than those co-treated with vehicle. Resveratrol modulated the cytokine-regulating pathway peroxisome proliferator activated receptor (PPAR)-γ/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and protected against DAC-induced decreases in the expression of the neuroplasticity biomarkers, brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), amino acid neurotransmitter receptors, and calmodulin-dependent protein kinase II (CaMKII). These results demonstrate the efficacy of resveratrol in preventing chemobrain and its association with cytokine modulation and neuroprotection.

Low-frequency hippocampal-cortical activity drives brain-wide resting-state functional MRI connectivity.

The hippocampus, including the dorsal dentate gyrus (dDG), and cortex engage in bidirectional communication. We propose that low-frequency activity in hippocampal-cortical pathways contributes to brain-wide resting-state connectivity to integrate sensory information. Using optogenetic stimulation and brain-wide fMRI and resting-state fMRI (rsfMRI), we determined the large-scale effects of spatiotemporal-specific downstream propagation of hippocampal activity. Low-frequency (1 Hz), but not high-frequency (40 Hz), stimulation of dDG excitatory neurons evoked robust cortical and subcortical brain-wide fMRI responses. More importantly, it enhanced interhemispheric rsfMRI connectivity in various cortices and hippocampus. Subsequent local field potential recordings revealed an increase in slow oscillations in dorsal hippocampus and visual cortex, interhemispheric visual cortical connectivity, and hippocampal-cortical connectivity. Meanwhile, pharmacological inactivation of dDG neurons decreased interhemispheric rsfMRI connectivity. Functionally, visually evoked fMRI responses in visual regions also increased during and after low-frequency dDG stimulation. Together, our results indicate that low-frequency activity robustly propagates in the dorsal hippocampal-cortical pathway, drives interhemispheric cortical rsfMRI connectivity, and mediates visual processing.

Diffusion tensor imaging reveals changes in the adult rat brain following long-term and passive moderate acoustic exposure.

This study investigated neuroanatomical changes following long-term acoustic exposure at moderate sound pressure level (SPL) under passive conditions, without coupled behavioral training. The authors utilized diffusion tensor imaging (DTI) to detect morphological changes in white matter. DTIs from adult rats (n = 8) exposed to continuous acoustic exposure at moderate SPL for 2 months were compared with DTIs from rats (n = 8) reared under standard acoustic conditions. Two distinct forms of DTI analysis were applied in a sequential manner. First, DTI images were analyzed using voxel-based statistics which revealed greater fractional anisotropy (FA) of the pyramidal tract and decreased FA of the tectospinal tract and trigeminothalamic tract of the exposed rats. Region of interest analysis confirmed (p < 0.05) that FA had increased in the pyramidal tract but did not show a statistically significant difference in the FA of the tectospinal or trigeminothalamic tract. The results of the authors show that long-term and passive acoustic exposure at moderate SPL increases the organization of white matter in the pyramidal tract.