In addition to classical spinocerebellar pathways, the cerebellum receives information from the spinal cord indirectly via spino-bulbar-cerebellar systems. One of the structures in this pathway is the lateral reticular nucleus (LRt). We performed series of experiments to investigate the organization and neurotransmitter content of spinoreticular tract (SRT) neurons in the lumbar spinal cord that project to the LRt. Three rats received injections of the b subunit of Cholera toxin (CTb) or Fluorogold (FG) within the left and right LRt. The majority of SRT cells (56–61%) were found within the contralateral medial intermediate gray matter where small numbers (7–10%) of double-labeled cells were also present on both sides of the cord. Six rats received unilateral spinal injections of CTb to label spinal projections to the LRt. Injections of FG were made also into the anterior lobe of the cerebellum to label LRt pre-cerebellar neurons. Terminals were found mainly ipsilateral to spinal injection sites within the central and ventrolateral regions of the LRt. Immunocytochemical analysis of SRT terminals revealed that the majority (75%) were contained vesicular glutamate transporter 2 but a minority (20%) contained the vesicular GABA transporter. The inhibitory subpopulation was found to be GABAergic, glycinergic, or contained both transmitters. Inhibitory and excitatory terminals were present within overlapping regions of the nucleus. Most CTb terminals contacting LRt pre-cerebellar neurons were excitatory (80%) whereas a minority were inhibitory and most cells (88%) received contacts from both inhibitory and excitatory terminals. This study shows that SRT axons in the LRt have the capacity to exert direct excitatory and inhibitory actions on LRt pre-cerebellar neurons. Thus spinal cord input has the capacity to facilitate or depress the activity of individual LRt cells which in turn adjust activity in the cerebellum to produce coordinated motor behaviors.

Bulbospinal systems (BS) originate from various regions of the brainstem and influence spinal neurons by classical synaptic and modulatory mechanisms. Our aim was to determine the brainstem locations of cells of origin of BS pathways passing through the medial longitudinal fasciculus (MLF) and the caudal ventrolateral medulla (CVLM). We also examined the transmitter content of spinal terminations of the CVLM pathway. Six adult rats received Fluorogold (FG) injections to the right intermediate gray matter of the lumbar cord (L1–L2) and the b-subunit of cholera toxin (CTb) was injected either into the MLF or the right CVLM (3 animals each). Double-labeled cells were identified within brainstem structures with confocal microscopy and mapped onto brainstem diagrams. An additional 3 rats were injected with CTb in the CVLM to label axon terminals in the lumbar spinal cord. Double-labeled cells projecting via the MLF or CVLM were found principally in reticular regions of the medulla and pons but small numbers of cells were also located within the midbrain. CVLM projections to the lumbar cord were almost exclusively ipsilateral and concentrated within the intermediate gray matter. Most (62%) of terminals were immunoreactive for the vesicular glutamate transporter 2 while 23% contained the vesicular GABA transporter. The inhibitory subpopulation was glycinergic, GABAergic or contained both transmitters. The proportions of excitatory and inhibitory axons projecting via the CVLM to the lumbar cord are similar to those projecting via the MLF. Unlike the MLF pathway, CVLM projections are predominantly ipsilateral and concentrated within intermediate gray but do not extend into motor nuclei or laminia VIII. Terminations of the CVLM pathway are located in a region of the gray matter that is rich in premotor interneurons; thus its primary function may be to coordinate activity of premotor networks.

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: Despite gigantic advances in medical research and development, chemotherapeutic resistance remains a major challenge for CNS tumors. The failure of complete eradication of CNS tumors has been correlated with the existence of several factors including over expression of transporter proteins. To date, 49 ABC-transporter proteins (ABC-TPs) are reported in humans, and the evidence of their strong association with chemotherapeutics’ influx, dissemination, and efflux in CNS tumors, is growing. Research studies in CNS tumor are implicating ABC-TPs as diagnostic, prognostic and therapeutic biomarkers that may be utilised in preclinical and clinical studies. With the current advancements in cell biology, molecular analysis of genomic and transcriptomic interplay, and protein homology-based drug-transporters’ interaction, our research approaches are streamlining the ABC-TPs’ roles in cancers and multidrug resistance. Potential ABC-TPs’ inhibitors for better clinical outcomes in CNS tumors have emerged. These include members of EZH2 inhibitors, which exhibit disparate level of selectivity for being a substrate for ABCB1 and ABCG2. Elacridar was shown to enhance chemo-sensitivity of Dasatanib and Imatinib in various glioma models. Tariquidar has improved Temozolomide’s effectiveness in CNS tumors. Although these inhibitors were shown to be effective in preclinical settings, their significant clinical outcomes have not been promising in clinical trials. Molecular evaluations of ABC-TPs and their drug-interactions are being pursued in various research labs, including ours, in an effort to better comprehend their biological mechanisms that are utilised for drug resistance, and to develop novel strategies to upsurge the clinical effectiveness of anticancer chemotherapeutics, which will ultimately improve the clinical outcomes.

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