Increased metabolic activity in the septum and habenula during stress is linked to subsequent expression of learned helplessness behavior

Uncontrollable stress can have a profound effect on an organism's ability to respond effectively to future stressful situations. Behavior subsequent to uncontrollable stress can vary greatly between individuals, falling on a spectrum between healthy resilience and maladaptive learned helplessness. It is unclear whether dysfunctional brain activity during uncontrollable stress is associated with vulnerability to learned helplessness; therefore, we measured metabolic activity during uncontrollable stress that correlated with ensuing inability to escape future stressors. We took advantage of small animal positron emission tomography (PET) and 2-deoxy-2[(18)F]fluoro-D-glucose ((18)FDG) to probe in vivo metabolic activity in wild type Sprague Dawley rats during uncontrollable, inescapable, unpredictable foot-shock stress, and subsequently tested the animals response to controllable, escapable, predictable foot-shock stress. When we correlated metabolic activity during the uncontrollable stress with consequent behavioral outcomes, we found that the degree to which animals failed to escape the foot-shock correlated with increased metabolic activity in the lateral septum and habenula. When used a seed region, metabolic activity in the habenula correlated with activity in the lateral septum, hypothalamus, medial thalamus, mammillary nuclei, ventral tegmental area, central gray, interpeduncular nuclei, periaqueductal gray, dorsal raphe, and rostromedial tegmental nucleus, caudal linear raphe, and subiculum transition area. Furthermore, the lateral septum correlated with metabolic activity in the preoptic area, medial thalamus, habenula, interpeduncular nuclei, periaqueductal gray, dorsal raphe, and caudal linear raphe. Together, our data suggest a group of brain regions involved in sensitivity to uncontrollable stress involving the lateral septum and habenula

Preservation of Astrocytic Coupling Prevents Epileptogenesis

Antiepileptic therapies are mainly based on drugs which target neuronal function. One third of epileptic patients do not respond adequately to these treatments and, importantly, all available drugs merely suppress seizures without curing the underlying disorder. Consequentially, new strategies for the development of antiepileptogenic drugs are urgently needed. Brain inflammation contributes to a loss of gap junction-mediated coupling between astrocytes, which is a causal event in the development of temporal lobe epilepsy (TLE). In a first step we assessed the effect of XPro1595 (a selective inhibitor of soluble TNF- alpha) and Anakinra (IL-1R antagonist) in situ in acute brain slices from epileptic mice and found that astrocytic coupling was restored. To investigate this in more detail, we checked the cytokine levels in the intracortical kainate (KA) model using ELISA. The results show elevated TNF-alpha levels immediately after KA-induced status epilepticus (SE), whereas IL-1beta was less prominent. This finding prompted us to assess the effect of solTNF-alpha/TNFR1 signalling cascade on astrocytic coupling. Hence, we investigated the effect of XPro1595 i.p. injection on astrocytic coupling and the development of TLE. The results show that XPro1595 given in vivo prior to KA injection prevented the loss of astrocytic gap junction coupling and thus the development of generalised spontaneous seizures and hippocampal sclerosis (HS) were prevented. Treatment with XPro1595 in vivo after KA injection rescued astrocytic coupling, significantly decreased chronic seizure frequency in the long-term and attenuated HS-specific morphological alterations. To confirm the effect of solTNF-alpha/TNFR1 signalling cascade on astrocytic coupling, we used transgenic TNFR1 KO animals in our epilepsy model. We could show that TNFR1 KO astrocytic coupling was unaltered after SE-induction, indicating that TNFR1 activation regulates astrocytic coupling strength. Furthermore, these animals showed significantly less seizure activity, demonstrating the importance of astrocytic coupling on the progression of TLE. However, incubation of acute brain slices from wildtype mice with TNF-alpha in situ revealed no impaired astrocytic coupling. Therefore, we suggest that a second mediator, like IL-1beta or a yet unknown molecule, might be needed to induce astrocytic uncoupling. In conclusion, this study demonstrates that solTNF-alpha/TNFR1 mediates astrocytic uncoupling and plays a key role in the development of TLE-HS. Rescuing astrocytic coupling might represent a new strategy to develop antiepileptogenic therapies. The present project elucidated the therapeutic potential of targeting astrocytic proteins in epilepsy and also shed further light on the mechanisms underlying the disorder

The Neuroprotective Effect of Gugijihwang-Tang on Trimethyltin-Induced Memory Dysfunction in the Rat

Gugijihwang-Tang (the herbal formula PM012), a decoction consisting of several herbs including Rehmanniae Radix Preparata, has been widely used as herbal treatment for dementia. In order to investigate the neuroprotective action of this prescription, we examined the effect of Gugijihwang-Tang on learning and memory using the Morris water maze and [F-18]FDG micro PET neuroimaging technique. After injection of trimethyltin (TMT, 8.0 mg/kg, i.p.), which is a potent toxicant that selectively kills cells in the central nervous system, rats were administered Gugijihwang-Tang (100 mg/kg, p.o.) daily for two weeks, followed by the Morris water maze tasks and [F-18]FDG micro PET neuroimaging. In Gugijihwang-Tang administered TMT-treated rats, they showed improved learning and memory abilities in water maze tasks and glucose metabolism, suggesting that Gugijihwang-Tang plays effectively positive role in the improvement of brain function including learning and memory after TMT-induced neurodegeneration. Taken together, our results suggested that the Gugijihwang-Tang should be useful for developing strategies protecting nervous system and improving brain function

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