RESUMO

Septo-hippocampal pathway, crucial for physiological functions and involved in epilepsy. Clinical monitoring during epileptogenesis is complicated. We aim to evaluate tissue changes after lesioning the medial septum (MS) of normal rats and assess how the depletion of specific neuronal populations alters the animals' behavior and susceptibility to establishing a pilocarpine-induced status epilepticus. Male Sprague-Dawley rats were injected into the MS with vehicle or saporins (to deplete GABAergic or cholinergic neurons; n = 16 per group). Thirty-two animals were used for diffusion tensor imaging (DTI); scanned before surgery and 14 and 49 days post-injection. Fractional anisotropy and apparent diffusion coefficient were evaluated in the fimbria, dorsal hippocampus, ventral hippocampus, dorso-medial thalamus, and amygdala. Between scans 2 and 3, animals were submitted to diverse behavioral tasks. Stainings were used to analyze tissue alterations. Twenty-four different animals received pilocarpine to evaluate the latency and severity of the status epilepticus 2 weeks after surgery. Additionally, eight different animals were only used to evaluate the neuronal damage inflicted on the MS 1 week after the molecular surgery. Progressive changes in DTI parameters in both white and gray matter structures of the four evaluated groups were observed. Behaviorally, the GAT1-saporin injection impacted spatial memory formation, while 192-IgG-saporin triggered anxiety-like behaviors. Histologically, the GABAergic toxin also induced aberrant mossy fiber sprouting, tissue damage, and neuronal death. Regarding the pilocarpine-induced status epilepticus, this agent provoked an increased mortality rate. Selective septo-hippocampal modulation impacts the integrity of limbic regions crucial for certain behavioral skills and could represent a precursor for epilepsy development.

Assuntos

Comportamento Animal , Imagem de Tensor de Difusão , Ratos Sprague-Dawley , Estado Epiléptico , Animais , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/patologia , Masculino , Sistema Límbico/patologia , Suscetibilidade a Doenças , Pilocarpina/toxicidade , Septo do Cérebro/patologia , Ratos , Hipocampo/patologia , Hipocampo/efeitos dos fármacos

RESUMO

Focal cortical dysplasias are a type of malformations of cortical development that are a common cause of drug-resistant focal epilepsy. Surgical treatment is a viable option for some of these patients, with their outcome being highly related to complete surgical resection of lesions visible in magnetic resonance imaging (MRI). However, subtle lesions often go undetected on conventional imaging. Several methods to analyze MRI have been proposed, with the common goal of rendering subtle cortical lesions visible. However, most image-processing methods are targeted to detect the macroscopic characteristics of cortical dysplasias, which do not always correspond to the microstructural disarrangement of these cortical malformations. Quantitative analysis of diffusion-weighted MRI (dMRI) enables the inference of tissue characteristics, and novel methods provide valuable microstructural features of complex tissue, including gray matter. We investigated the ability of advanced dMRI descriptors to detect diffusion abnormalities in an animal model of cortical dysplasia. For this purpose, we induced cortical dysplasia in 18 animals that were scanned at 30 postnatal days (along with 19 control animals). We obtained multi-shell dMRI, to which we fitted single and multi-tensor representations. Quantitative dMRI parameters derived from these methods were queried using a curvilinear coordinate system to sample the cortical mantle, providing inter-subject anatomical correspondence. We found region- and layer-specific diffusion abnormalities in experimental animals. Moreover, we were able to distinguish diffusion abnormalities related to altered intra-cortical tangential fibers from those associated with radial cortical fibers. Histological examinations revealed myelo-architectural abnormalities that explain the alterations observed through dMRI. The methods for dMRI acquisition and analysis used here are available in clinical settings and our work shows their clinical relevance to detect subtle cortical dysplasias through analysis of their microstructural properties.