Layer 1 NDNF+ Interneurons Control Bilateral Sensory Processing in a Layer-dependent Manner

ABSTRACTBilateral sensory information is indispensable for navigating the world. In most mammals, signals sensed by either side of the midline will ultimately reach the cortex where they will be integrated for perception and appropriate action selection. Even though information transferred across the hemispheres is routed through the corpus callosum, how and which microcircuits are key in integrating it is not well understood. Here we identify an essential role for layer 1 NDNF+ inhibitory cells of mice in integrating bilateral whisker-evoked information in an NMDA receptor-dependent manner. Direct connections from the contralateral cortex and the ipsilateral side activate NDNF+ neurons, which subsequently inhibit the late spiking activity of underlying layer 2/3 neurons, but not layer 5. Our results identify a feed-forward regulatory pathway for bilateral cortical sensory processing of upper layer cortical neurons actuated via layer 1 NDNF+ interneurons.

Study of the electrophysiological mechanisms of anticonvulsant action of the original levetiracetam analog the compound GIZH-290

The study used the method of cobalt epilepsy, which allows rats with long-term implanted electrodes in the cortical and subcortical structures of the brain to monitor the dynamics of the formation and migration of Epi-foci for a long time. It was found that in the control at the 1st stage of development of the Epi system, Epi activity is most pronounced in the electrocorticograms of the ipsilateral cortex, and at the 2nd, stable stage of development of the Epi system – in the contralateral cortex and subcortical structures. The compound GIZH-290 (the original structural analogue of levetiracetam) reduces the number of Epi discharges and their duration at the 2nd, stable stage of the development of the Epi system. The target structure of the GIZH – 290 compound was the hippocampus. The compound GIZH -290 selectively statistically significantly reduces both the number and duration of Epi – discharges only in the hippocampus and does not affect the foci of epileptic activity in the ipsi-and contralateral cortex and hypothalamus.

Corticofugal VIP Gabaergic Projection Neurons in the Mouse Auditory and Motor Cortex

Anatomical and physiological studies have described the cortex as a six-layer structure that receives, elaborates, and sends out information exclusively as excitatory output to cortical and subcortical regions. This concept has increasingly been challenged by several anatomical and functional studies that showed that direct inhibitory cortical outputs are also a common feature of the sensory and motor cortices. Similar to their excitatory counterparts, subsets of Somatostatin- and Parvalbumin-expressing neurons have been shown to innervate distal targets like the sensory and motor striatum and the contralateral cortex. However, no evidence of long-range VIP-expressing neurons, the third major class of GABAergic cortical inhibitory neurons, has been shown in such cortical regions. Here, using anatomical anterograde and retrograde viral tracing, we tested the hypothesis that VIP-expressing neurons of the mouse auditory and motor cortices can also send long-range projections to cortical and subcortical areas. We were able to demonstrate, for the first time, that VIP-expressing neurons of the auditory cortex can reach not only the contralateral auditory cortex and the ipsilateral striatum and amygdala, as shown for Somatostatin- and Parvalbumin-expressing long-range neurons, but also the medial geniculate body and both superior and inferior colliculus. We also demonstrate that VIP-expressing neurons of the motor cortex send long-range GABAergic projections to the dorsal striatum and contralateral cortex. Because of its presence in two such disparate cortical areas, this would suggest that the long-range VIP projection is likely a general feature of the cortex’s network.

GFAP positivity in neurons following traumatic brain injuries

Glial fibrillary acidic protein (GFAP) is a well-established astrocytic biomarker for the diagnosis, monitoring and outcome prediction of traumatic brain injury (TBI). Few studies stated an accumulation of neuronal GFAP that was observed in various brain pathologies, including traumatic brain injuries. As the neuronal immunopositivity for GFAP in Alzheimer patients was shown to cross-react with non-GFAP epitopes, the neuronal immunopositivity for GFAP in TBI patients should be challenged. In this study, cerebral and cerebellar tissues of 52 TBI fatalities and 17 controls were screened for immunopositivity for GFAP in neurons by means of immunohistochemistry and immunofluorescence. The results revealed that neuronal immunopositivity for GFAP is most likely a staining artefact as negative controls also revealed neuronal GFAP staining. However, the phenomenon was twice as frequent for TBI fatalities compared to non-TBI control cases (12 vs. 6%). Neuronal GFAP staining was observed in the pericontusional zone and the ipsilateral hippocampus, but was absent in the contralateral cortex of TBI cases. Immunopositivity for GFAP was significantly correlated with the survival time (r = 0.306, P = 0.015), but no correlations were found with age at death, sex nor the post-mortem interval in TBI fatalities. This study provides evidence that the TBI-associated neuronal immunopositivity for GFAP is indeed a staining artefact. However, an absence post-traumatic neuronal GFAP cannot readily be assumed. Regardless of the particular mechanism, this study revealed that the artefact/potential neuronal immunopositivity for GFAP is a global, rather than a regional brain phenomenon and might be useful for minimum TBI survival time determinations, if certain exclusion criteria are strictly respected.

Occipital ischaemic stroke after visual snow phenomenon – a case report

Background Persistent migraine with aura and neuroimaging examinations revealing ischaemia in the contralateral cortex may be associated with migrainous infarction. Despite being a neurological symptom that is distinct from migraine with aura, the visual snow phenomenon may also be associated with cerebral ischaemia. Here we describe a patient who reported short-lasting daily symptoms of visual snow that affected his entire visual field before becoming continuous and left-sided following acute occipital brain ischaemia. Case report In February 2017, a 74-year-old retired male was referred to our headache outpatient clinic with a diagnosis of recent right occipital cerebral ischaemia and migraine with aura. The patient reported visual snow symptoms that had changed from being bilateral and temporary to left-sided and permanent one day upon awakening; after being admitted to hospital a few hours later, he discovered he had had a stroke. He said he had never had any symptoms of migraine with aura. The visual snow phenomenon disappeared completely after about 1 year. Conclusions In our patient, a temporary daily visual snow phenomenon reversed to a persistent one. This phenomenon occurred in the part of his visual field that had been affected by the ischaemic occipital stroke, as typically happens in migrainous infarction. We hypothesise that the occipital lesion disrupted the inhibitory circuits, leading to a quadrantopic persistent visual snow. Since the mechanism may be the same as that observed in migrainous infarction, though with a different pathophysiology, it is possible to speculate that the aura in this case is the result, as opposed to the cause, of stroke in most patients.

Abstract TP103: Neonatal Stroke Alters Communication of Microglial Cells With Microglia-Derived Exosomes and Microvesicles

Inflammation modulates brain injury after perinatal arterial stroke. We previously demonstrated that microglial cells play an important role in protecting neonatal brain from acute stroke by phagocytosing dying neurons, attenuating cytokine accumulation and by protecting neurovascular integrity. Microglia may modulate injury in neonatal stroke via crosstalk between cells via other mechanisms, such as by releasing extracellular vesicles from microglia (MEV), including exosomes (MExo) and microvesicles (MMV). Aim: Elucidate the mechanisms of MEV communication with brain cells in injured neonatal brain and role of these vesicles in protection. Methods: Transient middle cerebral artery occlusion (tMCAO) was performed in postnatal day 9 (P9). Microglial cells were isolated by CD11b-conjugated beads from ischemic and contralateral cortex 24h after reperfusion and plated at same density for 96h. MEV were isolated by multi-step centrifugation (MMV) and ultra-centrifugation (MExo) and labeled with MiniClaret dye. Uptake of MEV from contralateral/ injured cortex by Iba1 + -cells from contralateral and injured regions was determined 10, 30 & 120min. Images co-stained with flotillin-1, which is strongly expressed in MMV but not in MExo, were analyzed using Volocity ® . Results: The uptake of MEV from injured cortex by microglia from injured cortex was significantly higher than uptake of contralateral-MEV by microglia from uninjured cortex (5-fold at 10min; p<0.0001) regardless of time. Uptake of MEV from injured regions by microglia from contralateral cortex and contralateral-MEV by microglia from injured cortex were low. While the number of ipsilateral and contralateral flotillin-1 + -MMV was similar, uptake of flotillin-1 - -MExo and ratio of ipsilateral MExo/MEV were significantly increase. Summary: Our data demonstrate selective enhancement of microglial communication with MEV from activated microglia after acute neonatal stroke as well as distinct MEV-subtype-dependent mechanisms of communication in injured brain. This mechanism could provide a better understanding of the role of microglia on the severity of neonatal stroke. Support: AHA17IRG33430004, RO1NS44025, RO1HL139685

Effect of lacosamide on epileptiform activity and structure-function relations in the brain of rats with chronic focal epilepsy

The aim was to study the effect of lacosamide on epileptiform activity (EрA) and structure-function relations in the brain in the course of development of the epileptic system in rats with cobalt-induced chronic epilepsy. Materials and methods. To model chronic focal epilepsy, we used topical applications of cobalt on the sensorimotor zone of the rat cortex. The effect of lacosamide (20 mg/kg) on the cobalt-induced epileptiform activity was analyzed in parallel with with the monitoring of spectral-coherent changes in the brain during the development of the epileptic system (ES). Results. In the first 30 minutes after the administration, lacosamide briefly enhanced the EрA in the hippocampus and ipsilateral cortex, and also strengthened the cortical-hippocampal (at stage 1) and cortical-hypothalamic connections (at stage 2). Two hours after the drug administration, a decrease in EрA was observed at stages 1 and 2 of the ES development, especially in the contralateral cortex and hippocampus. At all frequency ranges, the level of the inter-center connections decreased (most pronounced in the cortical-hippocampal links). Conclusion. The effect of lacosamide on EрA in the rat brain with cobalt-induced epileptogenic focus is characterized by a decrease in EрA, two hours after the drug administration. This effect is most expressed in the cortex and hippocampus, and is accompanied by a decrease in the level of the corticalhippocampal connections.

Selective inhibitory control of pyramidal neuron ensembles and cortical subnetworks by chandelier cells

ABSTRACTThe neocortex comprises multiple information processing streams mediated by subsets of glutamatergic pyramidal cells (PCs) that receive diverse inputs and project to distinct targets. How GABAergic interneurons regulate the segregation and communication among intermingled PC subsets that contribute to separate brain networks remains unclear. Here we demonstrate that a subset of GABAergic chandelier cells (ChCs) in the prelimbic cortex (PL), which innervate PCs at spike initiation site, selectively control PCs projecting to the basolateral amygdala (BLAPC) compared to those projecting to contralateral cortex (ccPC). These ChCs in turn receive preferential input from local and contralateralCCPCs as opposed toBLAPCs and BLA neurons (the PL-BLA network). Accordingly, optogenetic activation of ChCs rapidly suppressesBLAPCs and BLA activity in freely behaving mice. Thus, the exquisite connectivity of ChCs not only mediates directional inhibition between local PC ensembles but may also shape communication hierarchies between global networks.