Dissecting the role of subicular circuit in temporal lobe epilepsy / 中国药理学与毒理学杂志

OBJECTIVE Epilepsy is considered a cir-cuit-level dysfunction associated with imbalanced excita-tion-inhibition,it is therapeutically necessary to identify key brain regions and related circuits in epilepsy.The subic-ulum is an essential participant in epileptic seizures,but the circuit mechanism underlying its role remains largely elusive.METHODS Here we deconstruct the diversity of subicular circuits in mouse models of epilepsy.Fiber pho-tometry was used to detect intrinsic activities of subicular PV,SST-positive interneurons and CaMK Ⅱ α-positive pyramidal neurons.Optogenetics and chemogenetics were used to selectively active or inactive subicular neu-rons or their projecting terminals.We also used in vivo and in vitro electrophysiology to record membrane charac-teristics of single neuron in distinct sub-regions of the subiculum.Finally,single pulse test was used to detect synaptic transmission strength between the subiculum and its downstream target.RESULTS First,we found that two majority of subicular interneurons,which inner-vate local pyramidal neurons to constrain their excitability,PV and SST-positive neurons showcase distinct calcium dynamics during hippocampal seizures.This could be attributed to distinct neural inputs from para-hippocampal regions of these two neuronal types.During epileptogen-esis,PV and SST neurons undergo different circuit reor-ganization patterns,that is,remarkable increase of exter-nal input to subicular PV neurons are seen after seizures,while SST cells receive decimated neural input.As their downstream targets,excitatory subicular pyramidal neu-rons are also intrinsically activated during hippocampal seizures.Moreover,we found that the subiculum hetero-geneously controls the generalization of hippocampal sei-zures by projecting to different downstream regions.No-tably,anterior thalamus projecting subicular neurons bidi-rectionally mediate seizures,while entorhinal cortex-pro-jecting subicular neurons act oppositely in seizure modu-lation.These two subpopulations are structurally and functionally dissociable.An intrinsically enhanced hyper-polarization-activated current and robust bursting intensity in anterior thalamus-projecting neurons facilitate synaptic transmission,thus contributing to the generalization of hippocampal seizures.CONCLUSION These results demonstrate that subicular neurons and circuits have diverse roles in epilepsy,suggesting the necessity to pre-cisely target specific subicular circuits for effective treat-ment of epilepsy.

Inhibition of subicular seizure-labeled c-fos+ neurons alleviates cognitive deficit in epilepsy / 中国药理学与毒理学杂志

OBJECTIVE Cognitive deficit is a com-mon comorbidity in temporal lobe epilepsy(TLE)and that is not well controlled by current therapeutics.Currently,how epileptic seizure affects cognitive performance remains largely unclear.The subiculum is the major out-put of the hippocampus,which projects to entorhinal cor-tex and other more distinct brain regions.Physiologically,the subiculum codes spatial working memory and naviga-tion information including place,speed,and trajectory.Importantly,prior studies have noted the importance of the subiculum in the beginning,spreading,and generaliz-ing process of hippocampal seizure.How seizure-activated neurons in subiculum participate in cognitive impairment remains largely elusive.METHODS In this study,we sought to label the subicular seizure-activated c-fos+ neu-rons with a special promoter with enhanced synaptic activity-responsive element E-SARE in the subiculum,combined with chemogenetics and designer receptors exclusively activated by designer drugs(DREADDs),Ca2+ fiber photometry approaches,and behavioral tasks,to reveal the role of these neurons in cognitive impairment in epilepsy.RESULTS We found that chemogenetic inhibi-tion of subicular seizure-tagged c-fos+ neurons(mainly CaMK Ⅱ α+ glutamatergic neurons)alleviates seizure generalization and improves cognitive performance in the hippocampal CA3 kindling TLE model.While inhibition of seizure-labeled c-fos+ GABAergic interneuron shows no effect on seizure and cognition.As a comparison,che-mogenetic inhibition of the whole subicular CaMK Ⅱ α+ neuron impairs cognitive function in na?ve mice in basal condition.Notably,inhibition of subicular seizure-tagged c-fos+ neurons enhances the recruitment of cognition-responsive c-fos+ neurons via increasing neural excitability during cognition tasks.CONCLUSION Our results dem-onstrate that subicular seizure-activated c-fos+ neurons contribute to cognitive impairment in TLE,suggesting sei-zure-tagged c-fos+ neurons as the potential therapeutic target to alleviate cognitive impairment in TLE.

Basal Forebrain Cholinergic Innervation Induces Depression-Like Behaviors Through Ventral Subiculum Hyperactivation / 神经科学通报·英文版

Malfunction of the ventral subiculum (vSub), the main subregion controlling the output connections from the hippocampus, is associated with major depressive disorder (MDD). Although the vSub receives cholinergic innervation from the medial septum and diagonal band of Broca (MSDB), whether and how the MSDB-to-vSub cholinergic circuit is involved in MDD is elusive. Here, we found that chronic unpredictable mild stress (CUMS) induced depression-like behaviors with hyperactivation of vSub neurons, measured by c-fos staining and whole-cell patch-clamp recording. By retrograde and anterograde tracing, we confirmed the dense MSDB cholinergic innervation of the vSub. In addition, transient restraint stress in CUMS increased the level of ACh in the vSub. Furthermore, chemogenetic stimulation of this MSDB-vSub innervation in ChAT-Cre mice induced hyperactivation of vSub pyramidal neurons along with depression-like behaviors; and local infusion of atropine, a muscarinic receptor antagonist, into the vSub attenuated the depression-like behaviors induced by chemogenetic stimulation of this pathway and CUMS. Together, these findings suggest that activating the MSDB-vSub cholinergic pathway induces hyperactivation of vSub pyramidal neurons and depression-like behaviors, revealing a novel circuit underlying vSub pyramidal neuronal hyperactivation and its associated depression.

Endoscopic evaluation of middle ear anatomic variations in autopsy series: analyses of 204 ears / Avaliação endoscópica das variações anatômicas da orelha média em uma série de autópsias: análise de 204 orelhas

Abstract Introduction Microsurgery of the ear requires complete evaluation of middle ear surgical anatomy, especially the posterior tympanic cavity anatomy. Preoperative assessment of the middle ear cavity is limited by the permeability of eardrum and temporal bone density. Therefore, middle ear exploration is an extremely useful method to identify structural abnormalities and anatomical variations. Objective The aim of this study is to determine anatomic variations of the middle ear in an autopsy series. Methods All evaluations were performed in the Forensic Medicine Institute Morgue Department. The cases over 18 years of age, with no temporal bone trauma and history of otologic surgery included in this study. Results One hundred and two cadavers were included in the study. The mean age was 49.08 ± 17.76 years. Anterior wall prominence of the external auditory canal was present in 27 of all cadavers (26.4%). The tympanic membrane was normal in 192 ears (94%) while several eardrum pathologies were detected in 12 ears (6%). Agenesis of the pyramidal eminence and stapedial tendon was found in 3 ears. While the ponticulus was bony ridge-shaped in 156 of 204 ears (76.4%), it was bridge-shaped in 25 ears (12.3%). The ponticulus was absent in 23 ears (11.3%). While complete subiculum was present in 136 of all ears (66.7%), incomplete subiculum was present in 21 ears (10.3%). Subiculum was absent in 47 ears (23%). Facial dehiscence was found in 32 ears and the round window niche was covered by a pseudomembrane in 85 ears (41.6%). A fixed footplate was present in 7.4% of all ears, and no persistent stapedial artery was seen in any cases. Conclusion The pseudomembrane frequency covering the round window niche was found different from reports in the literature. In addition, the frequency of the external auditory canal wall prominence has been reported for the first time.

Resumo Introdução A otomicrocirurgia requer avaliação completa da anatomia cirúrgica da orelha média, especialmente da anatomia da cavidade timpânica posterior. A avaliação pré-operatória da cavidade timpânica é limitada pela permeabilidade do tímpano e densidade do osso temporal. Portanto, a exploração da orelha média é um método extremamente útil para identificar anormalidades estruturais e variações anatômicas. Objetivo Determinar as variações anatômicas da orelha média em uma série de autópsias. Método Todas as avaliações foram realizadas no necrotério do Instituto Médico-Legal. Os casos com mais de 18 anos, sem trauma do osso temporal e história de cirurgia otológica foram incluídos neste estudo. Resultados Cento e dois cadáveres foram incluídos no estudo. A média de idade foi de 49,08 ± 17,76 anos. A proeminência da parede anterior do conduto auditivo externo estava presente em 27 de todos os cadáveres (26,4%). A membrana timpânica era normal em 192 orelhas (94%), enquanto várias alterações do tímpano foram detectadas em 12 orelhas (6%). Agenesia da eminência piramidal e do tendão do estapédio foi encontrada em 3 orelhas. Enquanto o pontículo tinha formato de crista óssea em 156 das 204 orelhas (76,4%), tinha o formato de ponte em 25 orelhas (12,3%). O pontículo estava ausente em 23 orelhas (11,3%). Enquanto o subículo completo estava presente em 136 de todas as orelhas (66,7%), encontrava-se incompleto em 21 orelhas (10,3%). O subículo estava ausente em 47 orelhas (23%). Deiscência facial foi encontrada em 32 orelhas e o nicho da janela redonda estava coberto por uma pseudomembrana em 85 orelhas (41,6%). A platina fixa foi observada em 7,4% de todas as orelhas e a artéria estapediana persistente não foi vista. Conclusão A frequência da pseudomembrana que cobre o nicho da janela redonda foi diferente daquela encontrada na literatura. Além disso, a frequência da proeminência da parede do canal auditivo externo foi relatada pela primeira vez.

Total neuron numbers in CA1-4 sectors of the dog hippocampus.

Background & objectives: Early reports addressed morphological asymmetry in the cross-sectional width of the rat hippocampus. The present study was aimed at counting total number of neurons in CA1-4 sectors and the subiculum of the dog hippocampus as well as investigating possible left /right and male/female asymmetry. Methods: Adult mongrel dogs (8 female and 5 male) were assessed by the right and left pawedness and sacrificed by exsanguinations. In each hippocampus dissected, the total neuron numbers of CAs and subiculum were estimated by the physical fractioning method. Results: Significant hemispheric asymmetries were found in the number of pyramidal cells of CA1, CA3/2, CA4 and the subiculum. Sex difference was also found in the subiculum, in favour of the males. Interpretation & conclusion: Our study indicated a left dominant asymmetry in males and right dominancy in females as well as no functional asymmetry in specific regions of the dog hippocampus. Further investigations are necessary to verify the hypothesis that hippocampal morphological asymmetries in normal subjects are functionally related in memory or in cognitive skills.