Stimulation of Anterior Thalamic Nuclei Protects Against Seizures and Neuronal Apoptosis in Hippocampal CA3 Region of Kainic Acid-induced Epileptic Rats

Background：The antiepileptic effect of the anterior thalamic nuclei （ANT） stimulation has been demonstrated;however,its underlying mechanism remains unclear.The aim of this study was to investigate the effect of chronic ANT stimulation on hippocampal neuron loss and apoptosis.Methods：Sixty-four rats were divided into four groups：The control group,the kainic acid （KA） group,the sham-deep brain stimulation （DBS） group,and the DBS group.KA was used to induce epilepsy.Seizure count and latency to the first spontaneous seizures were calculated.Nissl staining was used to analyze hippocampal neuronal loss.Polymerase chain reaction and Western blotting were conducted to assess the expression of caspase-3 （Casp3）,B-cell lymphoma-2 （Bcl2）,and Bcl2-associated X protein （Box） in the hippocampal CA3 region.One-way analysis of variance was used to determine the differences between the four groups.Results：The latency to the first spontaneous seizures in the DBS group was significantly longer than that in the KA group （27.50 ± 8.05 vs.16.38 ± 7.25 days,P =0.0005）.The total seizure number in the DBS group was also significantly reduced （DBS vs.KA group：11.75 ± 6.80 vs.23.25 ± 7.72,P =0.0002）.Chronic ANT-DBS reduced neuronal loss in the hippocampal CA3 region （DBS vs.KA group：23.58 ± 6.34 vs.13.13 ± 4.00,P =0.0012）.After chronic DBS,the relative mRNA expression level of Casp3 was decreased （DBS vs.KA group：1.18 ± 0.37 vs.2.09 ± 0.46,P =0.0003）,and the relative mRNA expression level of Bcl2 was increased （DBS vs.KA group：0.92 ± 0.21 vs.0.48 ± 0.16,P =0.0004）.The protein expression levels of CASP3 （DBS vs.KA group：1.25 ± 0.26 vs.2.49 ± 0.38,P 〈 0.0001） and BAX （DBS vs.KA group：1.57 ± 0.49 vs.2.80 ± 0.63,P =0.0012） both declined in the DBS group whereas the protein expression level of BCL2 （DBS vs.KA group：0.78 ± 0.32 vs.0.36 ± 0.17,P =0.0086） increased in the DBS group.Conclusions：This study demonstrated that chronic ANT stimulation could exert a neuroprotective effect on hippocampal neurons.This neuroprotective effect is likely to be mediated by the inhibition of apoptosis in the epileptic hippocampus.

Anterior thalamic nuclei deep brain stimulation inhibits mossy fiber sprouting via 3′,5′-cyclic adenosine monophosphate/protein kinase A signaling pathway in a chronic epileptic monkey model

Background:Anterior thalamic nuclei(ATN)deep brain stimulation(DBS)is an effective method of controlling epilepsy,especially temporal lobe epilepsy.Mossy fiber sprouting(MFS)plays an indispensable role in the pathogenesis and progression of epilepsy,but the effect of ATN-DBS on MFS in the chronic stage of epilepsy and the potential underlying mechanisms are unknown.This study aimed to investigate the effect of ATN-DBS on MFS,as well as potential signaling pathways by a kainic acid(KA)-induced epileptic model.Methods:Twenty-four rhesus monkeys were randomly assigned to control,epilepsy(EP),EP-sham-DBS,and EP-DBS groups.KA was injected to establish the chronic epileptic model.The left ATN was implanted with a DBS lead and stimulated for 8 weeks.Enzyme-linked immunosorbent assay,Western blotting,and immunofluorescence staining were used to evaluate MFS and levels of potential molecular mediators in the hippocampus.One-way analysis of variance,followed by the Tukeypost hoc correction,was used to analyze the statistical significance of differences among multiple groups.Results:ATN-DBS is found to significantly reduce seizure frequency in the chronic stage of epilepsy.The number of ectopic granule cells was reduced in monkeys that received ATN stimulation(P<0.0001).Levels of 3′,5′-cyclic adenosine monophosphate(cAMP)and protein kinase A(PKA)in the hippocampus,together with Akt phosphorylation,were noticeably reduced in monkeys that received ATN stimulation(P=0.0030 andP=0.0001,respectively).ATN-DBS also significantly reduced MFS scores in the hippocampal dentate gyrus and CA3 sub-regions(allP<0.0001).Conclusion:ATN-DBS is shown to down-regulate the cAMP/PKA signaling pathway and Akt phosphorylation and to reduce the number of ectopic granule cells,which may be associated with the reduced MFS in chronic epilepsy.The study provides further insights into the mechanism by which ATN-DBS reduces epileptic seizures.

Functional and Neural Mechanisms of Out-of-Body Experiences: Importance of Retinogeniculo-Cortical Oscillations

Current research on the various forms of autoscopic phenomena addresses the clinical and neurological correlates of out-of-body experiences, autoscopic hallucinations, and heautoscopy. Yet most of this research is based on functional magnetic resonance imaging results and focuses predominantly on abnormal cortical activity. Previously we proposed that visual consciousness resulted from the dynamic retinogeniculo-cortical oscillations, such that the photoreceptors dynamically integrated with visual and other vision-associated cortices, and was theorized to be mapped out by photoreceptor discs and rich retinal networks which synchronized with the retinotopic mapping and the associated cortex. The feedback from neural input that is received from the thalamus and cortex via retinogeniculo-cortical oscillations and sent to the retina is multifold higher than feed-forward input to the cortex. This can effectively translate into out-of-body experiences projected onto the screen formed by the retina as it is perceived via feedback and feed-forward oscillations from the reticular thalamic nucleus, or “internal searchlight”. This article explores the role of the reticular thalamic nucleus and the retinogeniculo-cortical oscillations as pivotal internal components in vision and various autoscopic phenomena.

ACETYLCHOLINESTERASE HISTOCHEMISTRY OF THE THALAMUS IN THE PRIMATE

Objective To observe the distribution of acetylcholinesterase activity in the thalamus of the monkey.Methods Histochemical method was used to detect the acetylcholinesterase activity in the thalamus.Results Acetylcholinesterase was found to be inhomogeneous distribution in the primate thalamus and to reveal previously uncovered inhomogeneity within certain thalamic nuclei and their subdivisions. The medial, ventral and posterior nuclear groups displayed markedly uneven acetylcholinesterase reaction.In the mediodorsal nucleus,three distinct sbudivisions were revealed by acetylcholinesterase histochemistry, medial magnocellular part, ventral sector of central parvicellular part and dorsolateral sector of lateral pars multiformity showed weak, moderate and strong acetylcholinesterase activity, respectively. In the ventral nuclear group, acetylcholinesterase histochemistry was strong in the medial part of ventral posterior nucleus, moderate in the magnocellular part of ventral anterior, caudal, medial, oral and pars postrema parts of ventral lateral nucleus, as well as lateral part of ventral posterior nucleus, poor and weak in the inferior part of ventral posterior nucleus, par compacta of the medial part of ventral posterior nucleus and parvicellular part of ventral anterior nucleus. In the pulvinar nucleus, acetylcholinesterase reaction ranged from weak, moderate to strong in the parts of the oral, medial and lateral, as well as inferior of this nucleus, respectively. Regional variations of acetylcholinesterase activity within the thalamic nuclei and their subdivisions can help to identify them by acetylcholinesterase histochemistry. In addition, the dark patches of strong acetylcholinesterase activity contrasting with a lighter surrounding matrix were revealed within the parvicellular part and pars multiformis of mediodorsal nucleus, paracentral nucleus, central lateral nucleus, pars postrema part of ventral lateral nucleus and medial habenula nucleus, as well as medial part of pulvinar necleus, respectively.Conclusion Acetylcholinesterase histochemistry can serve as useful marker for delineating the thalamic nuclei and their sbudivisions. The different distribution of acetylcholinesterase histochemistry implies the activity of thalamic nuclei may be modulated by cholinergic systems.

Behavioral Effects of Deep Brain Stimulation of the Anterior Nucleus of Thalamus, Entorhinal Cortex and Fornix in a Rat Model of Alzheimer＇s Disease

Background：Recent clinical and preclinical studies have suggested that deep brain stimulation （DBS） can be used as a tool to enhance cognitive functions.The aim of the present study was to investigate the impact of DBS at three separate targets in the Papez circuit,including the anterior nucleus of thalamus （ANT）,the entorhinal cortex （EC）,and the fornix （FX）,on cognitive behaviors in an Alzheimer＇s disease （AD） rat model.Methods：Forty-eight rats were subjected to an intrahippocampal injection ofamyloid peptides 1-42 to induce an AD model.Rats were divided into six groups：DBS and sham DBS groups of ANT,EC,and FX.Spatial learning and memory were assessed by the Morris water maze （MWM）.Recognition memory was investigated by the novel object recognition memory test （NORM）.Locomotor and anxiety-related behaviors were detected by the open field test （OF）.By using two-way analysis of variance （ANOVA）,behavior differences between the six groups were analyzed.Results：In the MWM,the ANT,EC,and FX DBS groups performed differently in terms of the time spent in the platform zone （F（2.23） =6.04,P ＜ 0.01）,the frequency of platform crossing （F（2,23） =11.53,P ＜ 0.001）,and the percent time spent within the platform quadrant （F（2,23） =6.29,P ＜ 0.01）.In the NORM,the EC and FX DBS groups spent more time with the novel object,although the ANT DBS group did not （F（2,23） =10.03,P ＜ 0.001）.In the OF,all of the groups showed a similar total distance moved （F（1.42） =1.14,P =0.29）and relative time spent in the center （F（2,42） =0.56,P =0.58）.Conclusions：Our results demonstrated that DBS of the EC and FX facilitated hippocampus-dependent spatial memory more prominently thanANT DBS.In addition,hippocampus-independent recognition memory was enhanced by EC and FX DBS.None of the targets showed side-effects of anxiety or locomotor behaviors.