Alterações morfofuncionais no complexo basolateral da amígdala e regiões adjacentes de ratos wistar audiogênicos

Abstract

Epilepsy is a brain disorder characterized by a permanent predisposition to seizures and by the neurobiological, cognitive, psychological and social outcomes of this condition. A relevant percentage of the population may develop recurrent spontaneous seizures accompanied by neuropsychiatric comorbidities such as anxiety, depression, psychosis and learning and memory deficits, some cases with no overt metabolic or structural cause. Many types of epilepsy have a genetic background. Wistar audiogenic rats (WAR) comprise a genetically selected audiogenic reflex epilepsy animal model obtained through inbreeding of susceptible rats from a Wistar breeding stock, presenting brainstem generalized tonic-clonic seizures when sporadically stimulated with a high-intensity acoustic stimulus and prosencephalic limbic seizures when repeatedly stimulated (audiogenic kindling). The inferior colliculus is the epileptogenic focus responsible for onset of audiogenic seizures. Basolateral amygdala (BLA), a nuclei complex known for its importance in emotional processing in rats and humans, is crucial for recruitment of temporal limbic structures of WARs such as hippocampus and cortex, integrating the epileptogenic circuit when assaulted by repeated induction of seizures, presenting a peculiar predisposition of its circuits to recruitment by ictal afterdischarges. On the other hand, the striate-nigro-tectal circuit, important for sensory-motor processing in rats and humans, modulates audiogenic susceptibility and seizure severity in WARs. Neurons responsive to non-convulsive acoustic stimuli with similar latency and evoked dynamics are found in BLA and CPu. Beyond predisposition to hypersynchronism of acoustic-limbic pathway, non-kindled WARs are more prone to seizure elicited by electric or pharmacological stimuli, showing broadly altered cholinergic and GABAergic systems. WARs also present altered organic development being smaller than resistant Wistar rats, bearing a hyperresponsive hypothalamus-pituitary-adrenal axis and a cardiovascular malfunction, and non-kindled animals display atypical exploratory behavior of new environments, evidence of motor/emotional malfunction. Epileptic patients often show hypo or hypertrophy of cerebral regions. Using multiunit muilti-electrode deep recording technic we assessed spontaneous unit activity and response spike frequency evoked by non-convulsive acoustic pulses of BLA and CPu neurons of adult male non-kindled audiogenic and resistant Wistar rats, searching for evidence of innate altered information processing within these structures. Using non-invasive brain imaging magnetic resonance technic we conducted a longitudinal morphometric study and measured total brain volume, tertiary auditory cortex thickness and width and height of a inferior colliculus slice of male and female rats aging 7, 14, 21, 28, 42 and 70 days to investigate brain development of WARs and possible morphometric alterations related to audiogenic susceptibility condition. After electrophysiological recordings and sorting of the waveforms, neurons were classified and grouped according to similar evoked temporal dynamics, namely response latency, duration and sustainability. Number of responsive bins, number of evoked and spontaneous spikes were the variables analyzed within and between strains. In CPu of WARs, short-latency and transient response neurons discharged longer and peaked later; short-latency transient response followed by later spikes neurons displayed shorter discharges, fired less immediately after stimuli onset and showed lower spontaneous activity; sustained short-latency CPu neurons response duration, number of spikes and spontaneous firing were not significantly different from resistant rats. Sustained discharge BLA neurons from WARs, on the other hand, displayed shorter responses and significantly greater spontaneous activity compared to resistant rats, evidence of a ceiling effect. From the longitudinal morphometric approach we verified that total brain volume, cortical thickness and bi-dimensional estimate of inferior colliculus relation with body weight varied across development, being greater on the 7th, 14th, 21st and 28th day of age in WARs compared to resistant rats, reaching similar levels by 70th day. Briefly, we verified that non-kindled WARs have altered auditory information processing in BLA and CPu, structures important to prosecephalic epileptogenesis and modulation of audiogenic seizures, respectively, and important to appropriate behavior in tasks which WAR present altered emotional and exploratory activity (GARCIA-CAIRASCO et al., 1998). The longitudinal study revealed a neural-sparing phenomenon, despite lower body weight and innate endocrine (UMEOKA et al., 2011) and cardiovascular malfunction, similar to models of malnourished rats. The present results add to the understanding of the relation between epileptic phenomena with polygenic background and brain alterations not necessarily associated with epileptogenic processes.