Spinal cord injury (SCI) is a devastating condition. Splenectomy may play a protective role in the development of SCI. However, little is known about whether the timing of splenectomy affects the outcome after SCI. Investigation into splenectomy after SCI would provide insight into how the timing can be selected following SCI to improve neurological outcomes. Rats were randomized into a sham group, a nonsplenectomized group (NonSPX), four splenectomized groups with the surgery performed immediately, 6 h, 12 h, and 24 h after SCI (SPX0, SPX6, SPX12, and SPX24, respectively). Rats were subjected to severe contusive SCI at the level of the third thoracic vertebra. At different time points following SCI, BBB score was used to assess the recovery of injury. The animals in each group were randomly selected for tissue collection at day 3, 14, and 28 after surgery. Then, immunohistochemistry of immunologic cells was performed and inflammatory mediators were determined. Our study showed that splenectomy within 6 h ...

Despite numerous studies examining the mechanisms of operant conditioning (OC), the diversity of OC plasticity loci and their synergism have not been examined sufficiently. In the well-characterized feeding neural circuit of Aplysia , in vivo and in vitro appetitive OC increases neuronal excitability and electrical coupling among several neurons leading to an increase in expression of ingestive behavior. Here we used the in vitro analogue of OC to investigate whether OC reduces the excitability of a neuron, B4, whose inhibitory connections decrease expression of ingestive behavior. We found OC decreased the excitability of B4. This change appeared intrinsic to B4 because it could be replicated with an analogue of OC in isolated cultures of B4 neurons. In addition to changes in B4 excitability, OC decreased the strength of B4’s inhibitory connection to a key decision-making neuron, B51. The OC-induced changes were specific without affecting the excitability of another neuron critical for feeding behavior, B...

Neonatal hydrocephalus presents with various degrees of neuroinflammation and long-term neurological deficits in surgically treated patients, provoking a need for additional medical treatment. We previously reported elevated neuroinflammation and severe periventricular white matter damage in the progressive hydrocephalus ( prh ) mutant which contains a point mutation in the Ccdc39 gene, causing loss of cilia-mediated unidirectional cerebrospinal fluid (CSF) flow. In this study, we identified cortical neuropil maturation defects such as impaired excitatory synapse maturation and loss of homeostatic microglia, and swimming locomotor defects in early postnatal prh mutant mice. Strikingly, systemic application of the anti-inflammatory small molecule bindarit significantly supports healthy postnatal cerebral cortical development in the prh mutant. While bindarit only mildly reduced the ventricular volume, it significantly improved the edematous appearance and myelination of the corpus callosum. Moreover, the tr...

Ferroptosis is a caspase-independent, iron-dependent form of regulated necrosis extant in traumatic brain injury, Huntington disease, and hemorrhagic stroke. It can be activated by cystine deprivation leading to glutathione depletion, the insufficiency of the antioxidant glutathione peroxidase-4, and the hemolysis products hemoglobin and hemin. A cardinal feature of ferroptosis is extracellular signal-regulated kinase (ERK)1/2 activation culminating in its translocation to the nucleus. We have previously confirmed that the mitogen-activated protein (MAP) kinase kinase (MEK) inhibitor U0126 inhibits persistent ERK1/2 phosphorylation and ferroptosis. Here, we show that hemin exposure, a model of secondary injury in brain hemorrhage and ferroptosis, activated ERK1/2 in mouse neurons. Accordingly, MEK inhibitor U0126 protected against hemin-induced ferroptosis. Unexpectedly, U0126 prevented hemin-induced ferroptosis independent of its ability to inhibit ERK1/2 signaling. In contrast to classical ferroptosis in...

Alzheimer disease (AD) is a debilitating dementia characterized by progressive memory loss and aggregation of amyloid-β-protein (Aβ) into amyloid plaques in patient brain. Mutations in presenilin (PS) lead to abnormal generation of Aβ, which is the major cause of familial AD (FAD) and apolipoprotein E4 (ApoE4) is the major genetic risk factor for sporadic AD (SAD) onset. However, whether dysfunction of PS is involved in the pathogenesis of SAD is largely unknown. We found that ApoE secretion was completely abolished in PS-deficient cells and markedly decreased by inhibition of γ-secretase activity. Blockade of γ-secretase activity by a γ-secretase inhibitor, DAPT, decreased ApoE secretion, suggesting an important role of γ-secretase activity in ApoE secretion. Reduced ApoE secretion is also observed in nicastrin (NCT) deficient cells with reduced γ-secretase activity. PS deficiency enhanced nuclear translocation of ApoE and binding of ApoE to importin α4, a nuclear-transport receptor. Moreover, expression ...

The perception of control over a stressful experience may determine its impacts and generate resistance against future stressors. Although the medial prefrontal cortex (PFC) and the hippocampus (HPC) are implicated in the encoding of stressor controllability, the neural dynamics underlying this process are unknown. Here, we recorded HPC and PFC neural activities in male rats during the exposure to controllable, uncontrollable, or no shocks and investigated electrophysiological predictors of escape performance upon exposure to subsequent uncontrollable shocks. We were able to accurately discriminate stressed from nonstressed animals and predict resistant (R) or helpless (H) individuals based on hippocampal-cortical oscillatory dynamics. Remarkably, R animals exhibited an increase in theta power during CS, while H exhibited a decrease. Furthermore, R exhibited higher HPC to PFC θ synchronization during stress. Notably, HPC-PFC θ connectivity in the initial stress exposure showed strong correlations with esca...

Ankyrin scaffolding proteins are critical for membrane domain organization and protein stabilization in many different cell types including neurons. In the cerebellum, Ankyrin-R (AnkR) is highly enriched in Purkinje neurons, granule cells, and in the cerebellar nuclei (CN). Using male and female mice with a floxed allele for Ank1 in combination with Nestin-Cre and Pcp2-Cre mice, we found that ablation of AnkR from Purkinje neurons caused ataxia, regional and progressive neurodegeneration, and altered cerebellar output. We show that AnkR interacts with the cytoskeletal protein β3 spectrin and the potassium channel Kv3.3. Loss of AnkR reduced somatic membrane levels of β3 spectrin and Kv3.3 in Purkinje neurons. Thus, AnkR links Kv3.3 channels to the β3 spectrin-based cytoskeleton. Our results may help explain why mutations in β3 spectrin and Kv3.3 both cause spinocerebellar ataxia. SIGNIFICANCE STATEMENT Ankyrin scaffolding proteins localize and stabilize ion channels in the membrane by linking them to the ...