Short-Term Synaptic Plasticity Orchestrates the Response of Pyramidal Cells and Interneurons to Population Bursts

The synaptic drive from neuronal populations varies considerably over short time scales. Such changes in the pre-synaptic rate trigger many temporal processes absent under steady-state conditions. This paper examines the differential impact of pyramidal cell population bursts on post-synaptic pyramidal cells receiving depressing synapses, and on a class of interneuron that receives facilitating synapses. In experiment a significant shift of the order of one hundred milliseconds is seen between the response of these two cell classes to the same population burst. It is demonstrated here that such a temporal differentiation of the response can be explained by the synaptic and membrane properties without recourse to elaborate cortical wiring schemes. Experimental data is first used to construct models of the two types of dynamic synaptic response. A population-based approach is then followed to examine analytically the temporal synaptic filtering effects of the population burst for the two post-synaptic targets. The peak-to-peak delays seen in experiment can be captured by the model for experimentally realistic parameter ranges. It is further shown that the temporal separation of the response is communicated in the outgoing action potentials of the two post-synaptic cells: pyramidal cells fire at the beginning of the burst and the class of interneuron receiving facilitating synapses fires at the end of the burst. The functional role of such delays in the temporal organisation of activity in the cortical microcircuit is discusse

Short-term-plasticity orchestrates the response of pyramidal cells and interneurons to population bursts

The synaptic drive from neuronal populations varies considerably over short time scales. Such changes in the presynaptic rate trigger many temporal processes absent under steady-state conditions. This paper examines the differential impact of pyramidal cell population bursts on postsynaptic pyramidal cells receiving depressing synapses, and on a class of interneuron that receives facilitating synapses. In experiments a significant shift of the order of of one hundred milliseconds is seen between the response of these two cell classes to the same population burst. It is demonstrated here that such a temporal differentiation of the response can be explained by the synaptic and membranme properties without recourse to elaborate cortical wiring schemes

Neurotrophic receptor TrkB activation as an orchestrator of neuronal plasticity

Structural brain plasticity is an essential process to adjust maladapted networks, but it dramatically declines after closure of the critical periods during early postnatal life. Growing evidence suggests, however, that certain interventions, such as environmental enrichment and antidepressant treatment, can reinstate a network plasticity that is similar to that observed during the critical periods. Chronic treatment with the antidepressant fluoxetine, for example, can reopen visual cortex plasticity when combined with monocular deprivation. Further, it promotes the erasure of previously acquired fear memory when combined with extinction training. Fluoxetine can bind to and activate the neurotrophic TrkB receptor and can therefore regulate the downstream pathway to induce synaptic plasticity. Considering that TrkB receptors are expressed in essentially all neurons, the question to be answered is through which neuronal subpopulation are the plasticity effects regulated within these two circuitries. Visual cortex plasticity is tightly regulated by the inhibitory Parvalbumin (PV)-specific GABAergic network, which highly expresses TrkB receptors. During the critical periods TrkB’s ligand BrainDerived Neurotrophic Factor (BDNF) promotes the maturation of PV interneurons, thereby stimulating a precocious onset of critical periods. Hence, our first aim was to understand TrkB actions specifically in PV interneurons and their subsequent effects on visual cortex plasticity during adulthood. We used optically activated TrkB (optoTrkB) expressed only in PV interneurons of the visual cortex and found that optoTrkB activation by light combined with monocular deprivation is sufficient to induce ocular dominance plasticity. Strikingly, optoTrkB activation rapidly induces LTP in layer II/III of the visual cortex after theta burst stimulation (TBS). This potentiation in excitatory transmission is mediated by rapid decreases in the intrinsic excitability of PV regulated by reduced expressions of Kv3.1 and Kv3.2 mRNA. In addition, optoTrkB activation promotes the removal of perineuronal nets (PNNs) and shifts the PV and PNN networks into a plastic, immature configuration. Conversely, deleting TrkB from PV interneurons and using chronic fluoxetine treatment to pharmacologically induce plasticity prevented the effects of fluoxetine treatment. Our second aim was to identify the effects of optoTrkB activation expressed specifically in pyramidal neurons of the ventral hippocampus on the fear circuitry. We therefore directed the expression of optoTrkB to pyramidal neurons of the ventral hippocampus. During fear extinction optoTrkB was activated with light, and spontaneous recovery and fear renewal were tested one and three (remote memory) weeks after extinction training. We found that optoTrkB activation during extinction training promoted the erasure of remote fear memory. This effect was accompanied by increased LTP expression after brief TBS stimulation. Finally, fluoxetine and methylmercury (MeHg) are a common intervention and stressor, respectively, in our society, and exposure to either during pregnancy is known to impact brain development and functioning. An altered critical period can result in impairments that are retained into adulthood. Our aim was to understand how perinatal exposure to fluoxetine or MeHg affects the development of PV and PNNs, two well-established markers for the time course of critical periods, in the hippocampus and basolateral amygdala. We found that upon closure of the normal critical periods (P24) the number of PV and PNNs, and PV cell intensity increase. Perinatal fluoxetine treatment resulted in reduced expression of PNNs throughout critical periods, indicating a delayed closure. In contrast, perinatal MeHg exposure impaired the development of PV interneurons and PV expression at the onset of critical periods (P17), which were, however, restored upon critical period closure (P24), suggesting a delayed onset. Our results provide new evidence that TrkB activation in PV interneurons rapidly orchestrates cortical networks by reducing the intrinsic excitability of PV cells regulated by decreased expression of Kv3.1 and Kv3.2 channels, subsequently promoting excitatory transmission. In contrast, TrkB activation in pyramidal neurons of the ventral hippocampus also potentiates excitatory transmission. These opposite findings demonstrate that TrkB employs different mechanisms to increase the excitability of the neuronal network to induce plasticity. We propose that TrkB is a promising therapeutic target for the treatment of neuropsychiatric diseases that benefit from high plasticity modes. We further shed light on the effects of fluoxetine and MeHg exposure during pregnancy on the time course of the critical periods, which can help in developing better guidelines for the use and consumption of both during pregnancy.Aivojen rakenteellinen muovautuvuus on keskeinen prosessi hermoverkkojen hienosäädössä erityisesti silloin kun signalointi on jotenkin häiriintynyt. Tämän mekanismin aktiivisuus kuitenkin laskee huomattavasti pian syntymän jälkeen kriittisten periodien sulkeutuessa. Kasvava määrä todisteita viittaa siihen että jotkin interventiot, kuten elinympäristön rikastuttaminen tai masennuslääkehoito voivat palauttaa hermoverkkojen muovautumiskyvyn kriittisen periodin kaltaiselle tasolle. Esimerkiksi pitkäaikainen hoito masennuslääke fluoksetiinilla voi palauttaa muovautumiskyvyn näköaivokuorella, kun se yhdistetään silmän sulkemiseen. Tämän lisäksi fluoksetiinihoidon on todettu edistävän pelkomuiston häviämistä kun se yhdistetään häviämistä edistävään harjoitukseen. Fluoksetiini sitoutuu neurotrofiinireseptori TrkB:hen ja aktivoi sen ja siten säätelee synaptista muovatuvuutta lisääviä signalointireittejä. Vaikka TrkB-reseptori ilmenee laajasti hermostossa, on vielä epäselvää mikä hermosolupopulaatio välittää signaloinnin vaikutukset. Parvalbumiinia ilmentävät ja GABA-välittäjäainetta käyttävät välihermosolut muodostavat hermoverkon, joka säätelee tarkoin näköaivokuoren muovatuvuutta. Nämä solut ilmentävät myös suuria määriä TrkB- reseptoria. Kriittisen periodin aikana TrkB:n ligandi aivoperäinen hermokasvutekijä BDNF edistää PV- välittäjähermosolujen kypsymistä joka taas aikaistaa kriittisten periodien sulkeutumista. Ensimmäinen tavoitteemme oli siis ymmärtää TrkB:n toimintoja erityisesti PV-välihermosoluissa ja tämän vaikutuksia aikuisten hiirten näköaivokuoressa. Hyödynsimme tutkimuksissa valoaktivoituvaa TrkB-reseptoria (optoTrkB), jota ilmennettiin vain näköaivokuoren PV-välittäjähermosoluissa ja huomasimme, että optoTrkB:n aktivointi valolla yhdistettynä silmän sulkemiseen oli riittävä aikaansaamaan silmän dominanssimuutoksen. OptoTrkB:n aktivointi indusoi häkellyttävällä tavalla sähköstimulaation aikaansaamaa hermosolujen pitkäkestoista herkistymistä (LTP) näköaivokuoren kerroksella II/III. Tämä hermoverkkoja kiihdyttävän viestinnän aktivoituminen johtuu parvalbumiinisolujen aktivoitumiskynnyksen nopeasta laskusta, jota säätelee kaliumkanavien vähentynyt ilmentyminen. Tämän lisäksi optoTrkB:n aktivointi edistää perineuronaalisten verkkojen (PNN) hajoamista ja kääntää PV:n ja PNN:n viestintäverkostot muuntumiskykyiseen tilaan. TrkB-reseptorin poistaminen PV-välihermosoluista taas estää fluoksetiinihoidon farmakologiset vaikutukset hermoverkkojen muovautumiskykyyn. Toinen tavoitteemme oli tutkia optoTrkB-aktivaation vaikutuksia ventraalisen hippokampuksen pyramidisoluissa hermoverkossa, joka välittää pelkosignaaleja. OptoTrkB aktivoitiin valolla samalla, kun pelkoreaktiota hälvennettiin, minkä jälkeen spontaania toipumista ja pelon uusiutumista seurattiin yhden ja kolmen viikon päästä pelonhälventämisharjoituksista. Ilmeni, että optoTrkB:n aktivointi yhdessä pelon hälventämisharjoituksen kanssa edistää pelkomuiston häviämistä. Tämän vaikutuksen lisäksi LTP:n ilmentymisen todettiin kohonneen lyhyen sähköstimulaation jälkeen. Fluoksetiini ja metyylielohopea (MeHg) vaikuttavat kumpikin eri lailla todistetusti aivojen kehitykseen ja toimintaan kun niille altistutaan raskauden aikana. Muuntunut kriittinen periodi voi johtaa vielä aikuisuudessakin ilmeneviin heikentyneisiin toimintoihin. Tavoitteenamme oli ymmärtää, miten syntymänaikainen altistuminen fluoksetiinille tai metyylielohopealle vaikuttaa PV:n ja PNN:n kehitykseen, sillä molemmat ovat vakiintuneita kriittisen periodin ajoitukseen liittyviä merkkiaineita hippokampuksessa ja mantelitumakkeessa. Selvisi, että normaalin kriittisen periodin sulkeutuessa (P24) PV-solujen intensiteetti kasvoi kuten myös PV:n ja PNN:n määrä. Syntymänaikainen fluoksetiinikäsittely johti vähentyneeseen PNN:n ilmentymiseen läpi koko kriittisen periodin, mikä viittaa periodin viivästyneeseen sulkeutumiseen. Metyylielohopealle altistuminen taas heikensi PV-välittäjähermosolujen kehitystä ja PV:n ilmentymistä kriittisen periodin alussa (P17), mikä kuitenkin palautui normaalitasolle periodin sulkeutuessa, viitaten viivästyneeseen kriittisen periodin alkuun. Tuloksemme osoittavat, että TrkB-reseptorin aktivaatio PV-välittäjähermosoluissa nopeasti orkestroi aivokuoren hermoverkkoja madaltamalla PV-solujen stimulointikynnystä kaliumkanavien vähentyneen ilmentymisen välityksellä, mikä taas edistää kiihdyttävää viestinvälitystä. Toisaalta TrkB-reseptorin aktivointi ventraalisen hippokampuksen pyramiidisoluissa vahvistaa niin ikään kiihdyttävää viestinvälitystä. Nämä TrkB:n vastakkaiset kiihdyttävissä ja hiljentävissä hermosoluissa osoittavat, että TrkB käyttää eri soluissa eri mekanismeja jotka kuitenkin molemmat madaltavat hermoverkkojen stimulointikynnystä ja siten edistävät muovautuvuutta. Esitämme TrkB-reseptorin olevan lupaava hoitokohde sellaisten neuropsykiatristen sairauksien hoidossa, joita lisääntynyt muovautuvuus parantaa. Tuloksemme auttavat myös ymmärtämään raskaudenaikaisen fluoksetiinille ja metyylielohopealle altistumisen vaikutuksia kriittisten periodien ajoittumiseen. Tätä voitaisiin käyttää hyväksi kun kehitetään näiden aineiden raskaudenaikaista käytöä ja altistumista koskevia säännöksiä ja ohjeita

Clique of functional hubs orchestrates population bursts in developmentally regulated neural networks

It has recently been discovered that single neuron stimulation can impact network dynamics in immature and adult neuronal circuits. Here we report a novel mechanism which can explain in neuronal circuits, at an early stage of development, the peculiar role played by a few specific neurons in promoting/arresting the population activity. For this purpose, we consider a standard neuronal network model, with short-term synaptic plasticity, whose population activity is characterized by bursting behavior. The addition of developmentally inspired constraints and correlations in the distribution of the neuronal connectivities and excitabilities leads to the emergence of functional hub neurons, whose stimulation/deletion is critical for the network activity. Functional hubs form a clique, where a precise sequential activation of the neurons is essential to ignite collective events without any need for a specific topological architecture. Unsupervised time-lagged firings of supra-threshold cells, in connection with coordinated entrainments of near-threshold neurons, are the key ingredients to orchestrateComment: 39 pages, 15 figures, to appear in PLOS Computational Biolog

Activity-dependent regulation of GABA release at immature mossy fibers-CA3 synapses: role of the Prion protein

In adulthood, mossy fibers (MFs), the axons of granule cells of the dentate gyrus (DG), release glutamate onto CA3 principal cells and interneurons. In contrast, during the first week of postnatal life MFs release -aminobutyric acid (GABA), which, at this early developmental stage exerts a depolarizing and excitatory action on targeted cells. The depolarizing action of GABA opens voltage-dependent calcium channels and NMDA receptors leading to calcium entry and activation of intracellular signaling pathways involved in several developmental processes, thus contributing to the refinement of neuronal connections and to the establishment of adult neuronal circuits. The release of GABA has been shown to be down regulated by several neurotransmitter receptors which would limit the enhanced excitability caused by the excitatory action of GABA. It is worth noting that the immature hippocampus exhibits spontaneous correlated activity, the so called giant depolarizing potentials or GDPs that act as coincident detector signals for enhancing synaptic activity, thus contributing to several developmental processes including synaptogenesis. GDPs render the immature hippocampus more prone to seizures. Here, I explored the molecular mechanisms underlying synaptic transmission and activity-dependent synaptic plasticity processes at immature GABAergic MF-CA3 synapses in wild-type rodents and in mice lacking the prion protein (Prnp0/0 mice). In the first paper, I studied the functional role of kainate receptors (KARs) in regulating GABA release from MF terminals. Presynaptic KARs regulate synaptic transmission in several brain areas and play a central role in modulating glutamate release at adult MF-CA3 synapses. I found that functional presynaptic GluK1 receptors are present on MF terminals where they down regulate GABA release. Thus, application of DNQX or UBP 302, a selective antagonist for GluK1 receptors, strongly increased the amplitude of MF-GABAA-mediated postsynaptic currents (GPSCs). This effect was associated with a decrease in failure rate and increase in PPR, indicating a presynaptic type of action. GluK1 receptors were found to be tonically activated by glutamate present in the extracellular space, since decreasing the extracellular concentration of glutamate with a glutamate scavenger system prevented their activation and mimicked the effects of KAR antagonists. The depressant effect of GluK1 on GABA release was dependent on pertussis toxin (PTx)-sensitive G protein-coupled kainate receptors since it was prevented when hippocampal slices were incubated in the presence of a solution containing PTx. This effect was presynaptic since application of UBP 302 to cells patched with an intracellular solution containing GDP S still potentiated synaptic responses. In addition, the depressant effect of GluK1 on GABA release was prevented by U73122, which selectively inhibits phospholipase C, downstream to G protein activation. Interestingly, U73122, enhanced the probability of GABA release, thus unveiling the ionotropic type of action of kainate receptors. In line with this, we found that GluK1 receptors enhanced MF excitability by directly depolarizing MF terminals via calcium-permeable cation channels. We also explored the possible involvement of GluK1 in spike time-dependent (STD) plasticity and we found that GluK1 dynamically regulate the direction of STD-plasticity, since the pharmacological block of this receptor shifted spike-time dependent potentiation into depression. The mechanisms underlying STD-LTD at immature MF-CA3 synapses have been investigated in detail in the second paper. STD-plasticity is a Hebbian form of learning which consists in bi-directional modifications of synaptic strength according to the temporal order of pre and postsynaptic spiking. Interestingly, we found that at immature mossy fibers (MF)-CA3 synapses, STD-LTD occurs regardless of the temporal order of stimulation (pre versus post or viceversa). However, as already mentioned, while STD-LTD induced by positive pairing (pre before post) could be shifted into STD-LTP after blocking presynaptic GluK1 receptors, STD-LTD induced by negative pairing (post before pre) relied on the activation of CB1 receptors. At P3 but not at P21, endocannabinoids released by the postsynaptic cell during spiking-induced membrane depolarization retrogradely activated CB1 receptors, probably expressed on MF terminals and persistently depressed GABA release in the rat hippocampus. Thus, bath application of selective CB1 receptor antagonists prevented STD-LTD. Pharmacological tools allow identifying anandamide as the endogenous ligand responsible of activity-dependent depressant effect. To further assess whether STD-LTD is dependent on the activation of CB1 receptors, similar experiments were performed on WT-littermates and CB1-KO mice. While in WT mice the pairing protocol produced a persistent depression of MF-GPSCs as in rats, in CB1-KO mice failed to induce LTD. Consistent with these data, in situ hybridization experiments revealed detectable levels of CB1 mRNA in the granule cell layer of P3 but not of P21mice. These experiments strongly suggest that at immature MF-CA3 synapses STD-LTD is mediated by CB1 receptors, probably transiently expressed, during a critical time window, on MF terminals. In the third paper, I studied synaptic transmission and activity dependent synaptic plasticity at immature MF-CA3 synapses in mice devoid of the prion protein (Prnp0/0). The prion protein (PrPC) is a conserved glycoprotein widely expressed in the brain and involved in several neuronal processes including neurotransmission. If converted to a conformationally altered form, PrPSc can cause neurodegenerative diseases, such as Creutzfeldt-Jakob disease in humans. Previous studies aimed at characterizing Prnp0/0 mice have revealed only mild behavioral changes, including an impaired spatial learning, accompanied by electrophysiological and biochemical alterations. Interestingly, PrPC is developmentally regulated and in the hippocampus its expression parallels the maturation of MF. Here, we tested the hypothesis that at immature (P3-P7) MF-CA3 synapses, PrPC interferes with synaptic plasticity processes. To this aim, the rising phase of Giant Depolarizing Potentials (GDPs), a hallmark of developmental networks, was used to stimulate granule cells in the dentate gyrus in such a way that GDPs were coincident with afferent inputs. In WT animals, the pairing procedure induced a persistent increase in amplitude of MF-GPSCs. In contrast, in Prnp0/0 mice, the same protocol produced a long-term depression (LTD). LTP was postsynaptic in origin and required the activation of cAMP-dependent PKA signaling while LTD was presynaptic and was reliant on G protein-coupled GluK1 receptor and protein lipase C downstream to G protein activation. In addition, at emerging CA3-CA1 synapses of PrPC-deficient mice, stimulation of Schaffer collateral failed to induce LTP, known to be PKA-dependent. Finally, we also found that LTD in Prnp0/0 mice was mediated by GluK1 receptors, since UBP 302 blocked its induction. These data suggest that in the immature hippocampus PrPC controls the direction of synaptic plasticity

What is memory? The present state of the engram

The mechanism of memory remains one of the great unsolved problems of biology. Grappling with the question more than a hundred years ago, the German zoologist Richard Semon formulated the concept of the engram, lasting connections in the brain that result from simultaneous "excitations", whose precise physical nature and consequences were out of reach of the biology of his day. Neuroscientists now have the knowledge and tools to tackle this question, however, and this Forum brings together leading contemporary views on the mechanisms of memory and what the engram means today

Multi-column multi-layer computational model of neocortex

We present a multi-layer multi-column computational model of neocortex that is built based on the activity and connections of known neuronal cell types and includes activity-dependent short term plasticity. This model, a network of spiking neurons, is validated by showing that it exhibits activity close to biology in terms of several characteristics: (1) proper laminar flow of activity; (2) columnar organization with focality of inputs; (3) low-threshold-spiking (LTS) and fast-spiking (FS) neurons function as observed in normal cortical circuits; and (4) different stages of epileptiform activity can be obtained with either increasing the level of inhibitory blockade, or simulation of NMDA receptor enhancement. The aim of this research is to provide insight into the fundamental properties of vertical and horizontal inhibition in neocortex and their influence on epileptiform activity. The developed model was used to test novel ideas about modulation of inhibitory neuronal types in a developmentally malformed cortex. The novelty of the proposed research includes: (1) design and implementation of a multi-layer multi-column model of the cortex with multiple neuronal types and short-time plasticity, (2) modification of the Izhikevich neuron model in order to model biological maximum firing rate property, (3) generating local field potential (LFP) and EEG signals without modeling multiple neuronal compartments, (4) modeling several known conditions to validate that the cortex model matches the biology in several aspects,(5) modeling different abnormalities in malformed cortex to test existing and to generate novel hypotheses

Nicotinic acetylcholine receptor modulation of attention behavior and prefrontal cortical circuits

Mansvelder, H.D. [Promotor

Exploring hybrid networks made by neurons and progenitor cells

Neuronal stem cells (NSCs) and primitive progenitors (NPCs) play an essential role in homeostasis of the central nervous system (CNS). Due to their ability to differentiate into specific lineages, the possibility to manipulate these cell types could have a tremendous impact on future therapeutic approaches for brain or spinal cord injuries or degenerative diseases charachterized by neuronal loss. Thus, the study of the pathways involved in self-renewal and lineage-specific differentiation of stem cells is a pillar step to generate specific cell types required for clinical applications. We focused on fetal NPCs, a more committed subpopulation of NSCs, which are mostly cultured in vitro as neurospheres given their ability to proliferate and differentiate in all neuronal cell types. We tested wheter fNPCs could integrate among post-mitotic neurons and communicate with them by culturing them in co-culture in vitro system. This possibility was investigated by co-culturing fNPCS within hippocampal neurons, within dopaminergic neurons, obtained from substantia nigra compacta (SNc) and ventral tegmental area (VTA) and within cortical astrocytes. Our results suggest the capability of fNPCs to differently change their phenotype and cell development depending on the neural circuit they interact with. We further examined the main players responsible for such changes, including the soluble component released by different cell types and the firing properties of neurons