Recent studies have revealed that mossy fiber axons of granule cells in the dentate gyrus undergo reorganization of their terminal projections in both animal models of epilepsy and human epilepsy. This synaptic reorganization has been demonstrated by the Timm method, a histochemical technique that selectively labels synaptic terminals of mossy fibers because of their high zinc content. It has been generally presumed that the reorganization of the terminal projections of the mossy fiber pathway is a consequence of axonal sprouting and synaptogenesis by mossy fibers. To evaluate this possibility further, the time course for development of Timm granules, which correspond ultrastructurally to mossy fiber synaptic terminals, was examined in the supragranular layer of the dentate gyrus at the initiation of kindling stimulation with an improved scoring method for assessment of alterations in Timm histochemistry. The progression and permanence of this histological alteration were similarly evaluated during the behavioral and electrographic evolution of kindling evoked by perforant path, amygdala, or olfactory bulb stimulation. Mossy fiber synaptic terminals developed in the supragranular region of the dentate gyrus by 4 d after initiation of kindling stimulation in a time course compatible with axon sprouting. The induced alterations in the terminal projections of the mossy fiber pathway progressed with the evolution of behavioral kindled seizures, became permanent in parallel with the development of longlasting susceptibility to evoked seizures, and were observed as long as 8 months after the last evoked kindled seizure. The results demonstrated a strong correlation between mossy fiber synaptic reorganization and the development, progression, and permanence of the kindling phenomenon.
Repeated kindled seizures induce long-lasting physiological and morphological alterations in the hippocampal formation. In the dentate gyrus (DG), the morphological alterations induced by kindled seizures include loss of polymorphic neurons in the hilus, mossy fiber axon sprouting, and synaptic reorganization of the mossy fiber pathway. In this study, quantitative stereological methods were used to determine the distribution and time course of neuronal loss induced by 3, 30, or 150 kindled generalized tonic-clonic seizures in hippocampal, limbic, and neocortical pathways. Neuronal loss was observed in the hilus of the DG and CA1 after three generalized tonic-clonic seizures, and progressed in these sites to 49% and 44% of controls after 150 seizures. Neuronal loss was also observed in CA3, entorhinal cortex, and the rostral endopyriform nucleus after 30 seizures, and was detected in the granule cell layer and CA2 after 150 seizures. There was no evidence of neuronal loss in the somatosensory cortex after 150 seizures. The time course of the neuronal loss demonstrated selective vulnerability of hippocampal neuronal populations to seizure-induced injury, and suggests that even brief seizures may induce excitotoxic injury in vulnerable neuronal populations. Repeated brief seizures induced neuronal loss in a distribution that resembled hippocampal sclerosis, the most common lesion observed in human epilepsy. The results demonstrated that kindling induces alterations in neural circuitry in a variety of locations in the limbic system, and suggest that hippocampal sclerosis may be acquired in human epilepsy as a consequence of repeated seizures.
Kainic acid, an analog of the excitatory amino acid L-glutamate, induces acute hyperexcitability and permanent structural alterations in the hippocampal formation of the adult rat. Administration of kainic acid is followed by acute seizures in hippocampal pathways, neuronal loss in CA3 and the hilus of the dentate gyrus, and reorganization of the synaptic connections of the mossy fiber pathway. Rats with these hippocampal structural alterations have increased susceptibility to kindling. To evaluate the role of the acute seizures and associated hippocampal structural alterations in the development of this long-lasting susceptibility, rats that received intraventricular kainic acid were cotreated with phenobarbital (60 mg/kg, s.c., once daily). Treatment with this dose for 5 d after administration of kainic acid suppressed acute seizure activity, protected against excitotoxic damage in the dentate gyrus, reduced mossy fiber sprouting, and completely abolished the increased susceptibility to kindling associated with kainic acid. Brief treatment with phenobarbital modified the pattern of damage and synaptic reorganization in the dentate gyrus in response to seizure-induced injury, and altered the long-lasting functional effects associated with hippocampal damage. As phenobarbital treatment did not protect against neuronal damage in CA3 or other regions of the hippocampus, the circuitry of the dentate gyrus was implicated as a locus of cellular alterations that influenced the development of kindling. These observations are evidence that pharmacological intervention can prevent the development of epilepsy in association with acquired structural lesions, and suggest that pharmacological modification of cellular responses to injury can favorably alter long-term functional effects of CNS damage.
ImportanceDiversity in the biomedical research workforce is essential for addressing complex health problems. Female investigators and investigators from underrepresented ethnic and racial groups generate novel, impactful, and innovative research, yet they are significantly underrepresented among National Institutes of Health (NIH) investigators.ObjectiveTo examine the gender, ethnic, and racial distribution of super NIH investigators who received 3 or more concurrent NIH grants.Design, Setting, and ParticipantsThis cross-sectional study included a national cohort of NIH-funded principal investigators (PIs) from the NIH Information for Management, Planning, Analysis, and Coordination (IMPAC II) database from 1991 to 2020.ExposuresSelf-identified gender, race and ethnicity, annual number of NIH grant receipt, career stage, and highest degree.Main Outcomes and MeasuresDistribution of investigators receiving 3 or more research project grants, referred to as super principal investigators (SPIs), by gender, race, and ethnicity.ResultsAmong 33 896 investigators in fiscal year 2020, 7478 (22.01%) identified as Asian, 623 (1.8%) as Black, 1624 (4.8%) as Hispanic, and 22 107 (65.2%) as White; 21 936 (61.7%) identified as men; and 8695 (35.3%) were early-stage investigators. Between 1991 and 2020, the proportion of SPIs increased 3-fold from 704 (3.7%) to 3942 (11.3%). However, SPI status was unequal across gender, ethnic, and racial groups. Women and Black PIs were significantly underrepresented among SPIs, even after adjusting for career stage and degree, and were 34% and 40% less likely than their male and White colleagues, respectively, to be an SPI. Black women PIs were the least likely to be represented among SPIs and were 71% less likely to attain SPI status than White men PIs (adjusted odds ratio, 0.29; 95% CI, 0.21-0.41).Conclusions and RelevanceIn this cross-sectional study of a national cohort of NIH-funded investigators, the gender, ethnic, and racial gaps in receipt of multiple research project grants among NIH investigators was clearly apparent and warrants further investigation and interventions.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.