Abstract
Evidence suggests that the pathophysiology associated with epileptic susceptibility may disturb the functional connectivity of neural circuits and compromise the brain functions, even when seizures are absent. Although memory impairment is a common comorbidity found in patients with epilepsy, it is still unclear whether more caudal structures may play a role in cognitive deficits, particularly in those cases where there is no evidence of hippocampal sclerosis. This work used a genetically selected rat strain for seizure susceptibility (Wistar audiogenic rat, WAR) and distinct behavioral (motor and memory-related tasks) and electrophysiological (inferior colliculus, IC) approaches to access acoustic primary integrative network properties. The IC neural assemblies’ response was evaluated by auditory transient (focusing on bottom-up processing) and steady-state evoked response (ASSR, centering on feedforward and feedback forces over neural circuitry). The results show that WAR displayed no disturbance in motor performance or hippocampus-dependent memory tasks. Nonetheless, WAR animals exhibited significative impairment for auditory fear conditioning (AFC) along with no indicative of IC plastic changes between the pre-conditioning and test phases (ASSR coherence analysis). Furthermore, WAR’s IC response to transient stimuli presented shorter latency and higher amplitude compared with Wistar; and the ASSR analysis showed similar results for WAR and Wistar animals under subthreshold dose of pentylenetetrazol (pro-convulsive drug) for seizure-induction. Our work demonstrated alterations at WAR IC neural network processing, which may explain the associated disturbance on AFC memory.
Highlights
Cognitive functions are dependent on the integration of multiple and distributed neural populations across brain structures (Ward, 2003), but how exactly information is transferred between different processing networks from region to region is still a matter under study
Our work demonstrated that WAR’s seizure prone neural network displays alterations at the functional connectome level of the primary acoustic pathway; which may explain the associated auditory-related memory impairment observed for cued conditioning experiments
The contextual fear conditioning test evaluated hippocampus-dependent memory regarding aversive features (Figure 1A). Both strains demonstrated a significant increase at freezing behavior in the test session compared with preconditioning, with no statistical difference between strains (Interaction Time × Groups: F(1,18) = 0.4, p = 0.5; Time: F(1,18) = 148, p < 0.0001; Groups: F(1,18) = 0.2, p = 0.6; two-way analysis of variance (ANOVA)—Bonferroni’s post hoc test p > 0.05—Figure 1B)
Summary
Cognitive functions are dependent on the integration of multiple and distributed neural populations across brain structures (Ward, 2003), but how exactly information is transferred between different processing networks from region to region is still a matter under study. Several metrics of similarity have been developed in order to provide parameters to quantify the dynamics of the functional connectome (Bastos and Schoffelen, 2015), identifying both anatomically and temporally the transient exchange of information required for proper sensory-motor integration. Such a framework may provide a very efficient way (i.e., minimizing the number of connections) for transferring information throughout anatomically sequenced pathways of information processing (Buzsáki, 2006), but could lead to nonspecific network recruitment if lacking proper homeostatic control. The pathophysiology associated with epileptic susceptibility may disrupt the proper propagation of such specific discharge patterns leading to dysfunctional neural circuitry and memory impairment
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