Oxytocin, Compulsion and Epilepsy: Insights from a Complex Behavioral and Neuronal Networks Association

Abstract

18 19 Previously we have demonstrated that microinjection of oxytocin (OT) into the central nucleus of 20 amygdala (CeA) induces hypergrooming in Wistar rats, a model of compulsion. The Wistar 21 Audiogenic Rat (WAR) strain is a genetic model of generalized tonic-clonic seizures. Here we 22 quantified grooming behavior in WAR, with grooming scores, flowcharts and directed graphs of 23 syntactic and non-syntactic grooming chains, after bilateral administration of OT or saline (SAL) into 24 the CeA and investigated the association between hypergrooming and imunohistochemistry of Fos 25 activated compulsion networks and proposing a computational model of grooming behavior. The 26 activated networks, driven from a CeA OT-dependent grooming pattern, in both Wistar and WAR were 27 detected as Fos+ regions: orbitofrontal cortex, striatum, paraventricular nucleus of the hypothalamus, 28 dentate gyrus, substantia nigra compacta and reticulata. In conclusion we can drive hypergrooming in 29 WARs, defined previously as a model of ritualistic motor behavior in Wistar rats, with OT from CeA, a 30 limbic structure and one of the principal amygdala complex outputs. Furthermore, our current pioneer 31 behavioral and cellular description considers that hypergrooming (compulsion) in WARs is a 32 comorbidity because: (1) WARs have the highest grooming scores , when exposed only to novelty (2) 33 WARs have better grooming scores than Wistars after CeA-SAL, (3) WARs perform much better than 34 Wistars in OT-CeA-dependent highly stereotyped behavioral sequences, detected by flowcharts as a 35 combination of syntactic/non-syntactic grooming chains, (4) the behavioral sequences here 36 demonstrated for grooming and hypergrooming can be modeled as quite reliable Markov chains and (5) 37 with the exception of CeA-SAL injected animals, an exquisite map of brain Fos expression was 38 detected in typical cortico-striatal-thalamic-basal ganglia-cortical circuit, among new areas, driven by 39 OT-CeA. 40 41 -900 -Ribeirão Preto -SP 45 -Brazil 46 47 48 Author Summary 49 50 Grooming is a complex set of regular behavioral sequences in rodents that can be mimicked with 51 several pharmacological or molecular biology interventions. We have demonstrated previously that 52 microinjection of the brain peptide oxytocin into the amygdala, a limbic region, induces 53 hypergrooming in Wistar rats, a model of compulsion. The Wistar Audiogenic Rat strain is a genetic 54 model of generalized seizures, in fact a model of epilepsy. Here we quantified grooming behavior in 55 Wistar Audiogenic Rats, using several behavioral tools such as grooming scores, behavioral sequences 56 and graphs of grooming chains, after bilateral administration of the oxytocin or its control (saline) into 57 the amygdala. We also investigated the association between hypergrooming and activation of 58 compulsion networks, proposing a computational (virtual) model of grooming behavior. Basically we 59 were able to detect activated networks, driven from amygdala and the consequent oxytoci...

Neuroendocrine changes in the hypothalamic‐neurohypophysial system in the Wistar audiogenic rat (WAR) strain submitted to audiogenic kindling

“…WARs have also demonstrated high expression of both heteronuclear and messenger RNA of Oxt in paraventricular nucleus. In line with our results, Marroni et al 41 showed that WARs had more OXT/Fos double‐labeling in paraventricular nucleus than Wistar rats in control conditions. Altogether, these findings indicate that the WAR strain has endogenous alterations in the oxytocinergic system, and the increase in oxytocin plasma levels observed may occur due to an association between high paraventricular nucleus Oxt gene expression and increased oxytocinergic neuronal activity.…”

“…Similarly, WARs also presented increased activity of oxytocin neurons 41 and Oxt expression in paraventricular nucleus, as demonstrated here. Therefore, this indicates that the paraventricular nucleus oxytocinergic neurons could be an integral part of the LiR in the WAR strain, being involved in their exploratory, anxiety‐related, social and compulsive behavioral changes 41,48,49 . However, in other models of limbic seizures, such as entorhinal cortex or amygdala electrical kindling, no changes in Oxt gene expression were found in supraoptic nuclei or paraventricular nucleus, probably due to the differences in neuroplasticity among models 10,27 .…”

“…In the kainic acid model of Status Epilepticus (mainly limbic seizures), paraventricular nucleus oxytocinergic neurons are more active 10 and present increased expression of m Oxt 47 . Similarly, WARs also presented increased activity of oxytocin neurons 41 and Oxt expression in paraventricular nucleus, as demonstrated here. Therefore, this indicates that the paraventricular nucleus oxytocinergic neurons could be an integral part of the LiR in the WAR strain, being involved in their exploratory, anxiety‐related, social and compulsive behavioral changes 41,48,49 .…”

Maternal behavior and the neonatal HPA axis in the Wistar Audiogenic Rat (WAR) strain: early life implications for a genetic animal model in epilepsy

“…Behavioral changes that emerge after the postpartum period are mediated by a wide variety of neurotransmitters such as dopamine and neurohormones such as oxytocin (OT) and ACTH. WARs show higher ACTH secretion [28] and previous studies from our laboratory have suggested that WARs, could present alterations in the OT system [50], which might be related to a naturally excessive grooming when exposed to a novel environment. As a consequence, it would be interesting to study neurohormonal brain circuits in WARs and verify how they contribute to specific behaviors directed to the pup care, like LG and retrieving.…”

Maternal behavior and the neonatal HPA axis in the Wistar Audiogenic Rat (WAR) strain: Early-life implications for a genetic animal model in epilepsy

“…Behavioral changes that emerge after the postpartum period are mediated by a wide variety of neurotransmitters such as dopamine and neurohormones such as oxytocin (OT) and ACTH. WARs show higher ACTH secretion [28] and previous studies from our laboratory have suggested that WARs, could present alterations in the OT system [50], which might be related to a naturally excessive grooming when exposed to a novel environment. As a consequence, it would be interesting to study neurohormonal brain circuits in WARs and verify how they contribute to specific behaviors directed to the pup care, like LG and retrieving.…”