Female rats are resilient to the behavioral effects of maternal separation stress and exhibit stress-induced neurogenesis.

Early-life stress causes anxiogenesis and sensitivity of stress endocrine axis, facilitated by changes in the basolateral amygdala and hippocampal neurogenesis. In this report, we examined if male-like relationship between early-life stress and anxiety was recapitulated in female rats, along with related neurobiological substrates of the amygdala and the hippocampus. Maternal separation, a paradigm consistently utilized in male rats in most previously published scripts, did not cause similar behavioral consequences in females. Maternal separation caused an increase in adult hippocampal neurogenesis in females without causing substantial differences in dendritic arbors of the basolateral amygdala. Thus, female rats displayed remarkable resilience in the emotional consequences of early-life stress.

Early life maternal separation stress augmentation of limbic epileptogenesis: the role of corticosterone and HPA axis programming.

Early life stress causes long-lasting effects on the limbic system that may be relevant to the development of mesial temporal lobe epilepsy (MTLE) and its associated psychopathology. Recent studies in rats suggest that maternal separation (MS), a model of early life stress, confers enduring vulnerability to amygdala kindling limbic epileptogenesis. However, the mechanisms underlying this remain unknown. Here, we tested whether hypothalamic-pituitary-adrenal (HPA) axis hyper-reactivity induced by MS - specifically the excessive secretion of corticosterone following a seizure - was involved in this vulnerability. In adult female rats subjected to MS from postnatal days 2-14, seizure-induced corticosterone responses were significantly augmented and prolonged for at least two hours post-seizure, compared to control early-handled (EH) rats. This was accompanied by reduced seizure threshold (p<0.05) and increased vulnerability to the kindling-induced progression of seizure duration (p<0.05) in MS rats. Pre-seizure treatment with the corticosterone synthesis inhibitor, metyrapone (MET) (50mg/kgsc) effectively blocked seizure-induced corticosterone responses. When delivered throughout kindling, MET treatment also reversed the MS-induced reduction in seizure threshold and the lengthened seizure duration back to levels of EH rats. These observations suggest that adverse early life environments induce a vulnerability to kindling epileptogenesis mediated by HPA axis hyper-reactivity, which could have relevance for the pathogenesis of MTLE.

Chronic antidepressant treatment accelerates kindling epileptogenesis in rats.

OBJECTIVES: Due to the high comorbidity of epilepsy and depression, antidepressant treatment is commonly indicated for patients with epilepsy. Studies in humans and animal models suggest that selective serotonin reuptake inhibitors (SSRIs) may reduce seizure frequency and severity, and these drugs are generally considered safe for use in epilepsy. No studies have investigated the effects of SSRIs on epileptogenesis, the neurobiological process underlying the development of the epileptic state. METHODS: The effect of continuous infusion of the SSRI, fluoxetine (10mg/kg/day sc), versus vehicle control on amygdala kindling was examined in adult male Wistar rats. Seizure threshold and kindling rates were compared between SSRI-treated rats and controls. The study was then repeated examining the effect of a different SSRI, citalopram (10mg/kg/day sc), versus vehicle control. Hippocampal mRNA expression of the serotonin transporter (SERT) and the 5-HT1A receptor was examined in the brains of the rats post-mortem. RESULTS: Treatment with either fluoxetine or citalopram significantly accelerated kindling epileptogenesis, as evidenced by fewer stimulations to reach Class V seizures compared to their respective vehicle-treated group (p<0.01 for both drugs). Seizure duration was also increased in fluoxetine-treated rats. No differences in seizure threshold were observed between treatments (p>0.05). mRNA analysis did not reveal any molecular changes which were common to both treatments. CONCLUSIONS: The rate of epileptogenesis in rats is enhanced by chronic treatment with SSRIs. This could potentially have implications regarding the effect of SSRIs on the development or progression of human epilepsy.

Confounding neurodegenerative effects of manganese for in vivo MR imaging in rat models of brain insults.

PURPOSE: To examine the long-term consequences of manganese exposure due to the use of manganese-enhanced magnetic resonance imaging (MEMRI) in a model of closed head injury, the fluid-percussion injury (FPI) model. MATERIALS AND METHODS: Two groups of adult male Wistar rats (n = 72) were studied with either MEMRI, whereby rats receive MnCl(2) (100 mg/kg intraperitoneally) 24 hours prior to scanning, or standard MRI (sMRI) with no contrast agent. Rats from both groups underwent FPI or sham injury and were longitudinally assessed for 6 months for neurological toxicity using behavioral tests, EEG recording, and MRI scanning. RESULTS: Regardless of whether they received FPI, MEMRI animals showed progressive signs of cerebral toxicity compared with sMRI rats, including significantly reduced weight gain, progressive brain volume decrease, and increased anxiety and depressive-like behaviors. CONCLUSION: Long-term structural and functional consequences of using manganese as a contrast agent for MRI can confound experimental outcomes and must be taken into account when designing longitudinal imaging studies using manganese-enhanced MRI.

Early life stress as an influence on limbic epilepsy: an hypothesis whose time has come?

The pathogenesis of mesial temporal lobe epilepsy (MTLE), the most prevalent form of refractory focal epilepsy in adults, is thought to begin in early life, even though seizures may not commence until adolescence or adulthood. Amongst the range of early life factors implicated in MTLE causation (febrile seizures, traumatic brain injury, etc.), stress may be one important contributor. Early life stress is an a priori agent deserving study because of the large amount of neuroscientific data showing enduring effects on structure and function in hippocampus and amygdala, the key structures involved in MTLE. An emerging body of evidence directly tests hypotheses concerning early life stress and limbic epilepsy: early life stressors, such as maternal separation, have been shown to aggravate epileptogenesis in both status epilepticus and kindling models of limbic epilepsy. In addition to elucidating its influence on limbic epileptogenesis itself, the study of early life stress has the potential to shed light on the psychiatric disorder that accompanies MTLE. For many years, psychiatric comorbidity was viewed as an effect of epilepsy, mediated psychologically and/or neurobiologically. An alternative - or complementary - perspective is that of shared causation. Early life stress, implicated in the pathogenesis of several psychiatric disorders, may be one such causal factor. This paper aims to critically review the body of experimental evidence linking early life stress and epilepsy; to discuss the direct studies examining early life stress effects in current models of limbic seizures/epilepsy; and to suggest priorities for future research.