Auditory critical periods: A review from system’s perspective

AbstractThe article reviews evidence for sensitive periods in the sensory systems and considers their neuronal mechanisms from the viewpoint of the system’s neuroscience. It reviews the essential cortical developmental steps and shows its dependence on experience. It differentiates feature representation and object representation and their neuronal mechanisms. The most important developmental effect of experience is considered to be the transformation of a naive cortical neuronal network into a network capable of categorization, by that establishing auditory objects. The control mechanisms of juvenile and adult plasticity are further discussed. Total absence of hearing experience prevents the patterning of the naive auditory system with subsequent extensive consequences on the auditory function. Additional to developmental changes in synaptic plasticity, other brain functions like corticocortical interareal couplings are also influenced by deprivation. Experiments with deaf auditory systems reveal several integrative effects of deafness and their reversibility with experience. Additional to developmental molecular effects on synaptic plasticity, a combination of several integrative effects of deprivation on brain functions, including feature representation (affecting the starting point for learning), categorization function, top–down interactions and cross-modal reorganization close the sensitive periods and may contribute to their critical nature. Further, non-auditory effects of auditory deprivation are discussed. To reopen critical periods, removal of molecular breaks in synaptic plasticity and focused training therapy on the integrative effects are required

Cortical GABAergic Interneurons in Cross-Modal Plasticity following Early Blindness

Early loss of a given sensory input in mammals causes anatomical and functional modifications in the brain via a process called cross-modal plasticity. In the past four decades, several animal models have illuminated our understanding of the biological substrates involved in cross-modal plasticity. Progressively, studies are now starting to emphasise on cell-specific mechanisms that may be responsible for this intermodal sensory plasticity. Inhibitory interneurons expressing γ-aminobutyric acid (GABA) play an important role in maintaining the appropriate dynamic range of cortical excitation, in critical periods of developmental plasticity, in receptive field refinement, and in treatment of sensory information reaching the cerebral cortex. The diverse interneuron population is very sensitive to sensory experience during development. GABAergic neurons are therefore well suited to act as a gate for mediating cross-modal plasticity. This paper attempts to highlight the links between early sensory deprivation, cortical GABAergic interneuron alterations, and cross-modal plasticity, discuss its implications, and further provide insights for future research in the field

Microcircuit remodeling processes underlying learning in the adult

One of the most intriguing discoveries in neuroscience of the past decades has been showing that experience is able to induce structural modifications in cortical microcircuit that might underlie the formation of memories upon learning (for a review, see Caroni, Donato and Muller 2012). Hence, learning induces phases of synapse formation and elimination that are strictly regulated by a variety of mechanisms, which impact on cortical microcircuits affecting both excitatory and inhibitory neurons. Nevertheless, the extent to which specific configurations might be implemented to support specific phases of learning, as well as the impact of experience-induced structural modifications on further learning, is still largely unknown. Here, I explore how the remodeling of identified microcircuits in the mouse hippocampus and neocortex supports learning in the adult. In the first part, I identifiy a microcircuit module engaging VIP and Parvalbumin (PV) positive interneurons to regulate the state of the PV+ network upon experience. This defines states of enhanced or reduced structural plasticity and learning based on the distribution of PV intensity in the network. In the second part, I demonstrate how specific hippocampal subdivisions are exploited to learn subtasks of trial-and-errors forms of learning via the deployment of increasingly precise searching strategies, and sequential recruitment of ventral, intermediate, and dorsal hippocampus. In the third part, I highlight the existence of genetically matched subpopulations of principal cells in the hippocampus, which achieve selective connectivity across hippocampal subdivisions via matched windows of neurogenesis and synaptogenesis during development. In the fourth part, I investigate the maturation of microcircuits mediating feedforward inhibition in the hippocampus, and highlight windows during development for the establishment of the proper baseline configuration in the adult. Moreover, I identify a critical window for cognitive enhancement during hippocampal development. In the fifth part, I study how ageing affects the PV network in hippocampal CA3, providing evidence for which age related neuronal loss correlates to reduced incidental learning performances in old mice. Therefore, by manipulating the PV network early during life, I provide strategies to modulate cognitive decline

Mechanisms of ocular dominance plasticity in the juvenile and adult mouse visual cortex

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2011.Cataloged from PDF version of thesis. Vita.Includes bibliographical references (p. 171-185).Ocular dominance (OD) plasticity is a classic example of bidirectional experience-dependent plasticity in the primary visual cortex. This form of plasticity is most robust during early postnatal development (termed the "critical period"), when monocular deprivation (MD) leads to a rapid weakening of responses evoked through the deprived eye followed by a delayed strengthening of non-deprived eye inputs. It has been proposed that these bidirectional changes occur as a three-stage process: first, degradation of patterned visual input weakens deprived-eye responses via homosynaptic long-term depression (LTD); this is accompanied by a shift in the plasticity modification threshold (0m) that determines the direction of synaptic plasticity, such that synaptic strengthening is favored over synaptic weakening; finally, weak open-eye responses are strengthened via the mechanisms of homosynaptic long-term potentiation (LTP). Despite the growing evidence supporting this model of experience-dependent synaptic modification, the exact molecular and synaptic mechanisms that are responsible for these processes remain controversial. In my thesis work, I address three questions. First, I attempt to parse the relative contribution of excitatory and inhibitory processes to expression of the OD shift in order to understand how deprived-eye depression is expressed in the cortex. To address this, I first induce a shift in OD with 3 days of MD and then use several pharmacological methods to shut off cortical inhibitory synaptic transmission. I demonstrate that rapid deprived-eye depression is strongly expressed at excitatory thalamocortical synapses without any influences of polysynaptic intracortical inhibition. In the second part of my work, I try to resolve the nature/identity of the molecular mechanism that underlies the regulation of [theta]m. Using a transgenic mouse model, I find that a reduction in the NR2A/B subunit ratio of the N-methyl-d-aspartate (NMDA) receptor during MD alters the qualities of OD plasticity by impairing weakening of deprived-eye inputs and enhancing strengthening of open-eye inputs. These findings suggest that NMDAR subunit composition may specify the value and the rate of adjustment of synaptic 0m, which in turn determines the bidirectional cortical response to MD. The final portion of my thesis addresses the factors that limit OD plasticity beyond the critical period. I test the hypothesis that the developmental increase in intracortical GABAergic inhibitory synaptic transmission is a fundamental restricting factor for adult cortical plasticity and demonstrate that parvalbumin-expressing fast-spiking basket cells are specifically implicated in the absence of juvenile-like deprived-eye depression in adult mice.by Lena A. Khibnik.Ph.D

CELLULAR MECHANISMS UNDERLYING HOMEOSTATIC AND CROSS-MODAL PLASTICITY IN MOUSE PRIMARY VISUAL CORTEX

The brain has an essential ability to modify and reorganize synaptic connections according to experience. Sensory experience, in particular, is required for the formation of cortical circuits during early postnatal development and for their regulation throughout life. Synaptic connections are modified according to experience through two mechanisms, synapse-specific (Hebbian) and global (homeostatic) plasticity, which must work in harmony to achieve optimal processing. Sensory loss causes brain-wide adaptations that engage both types of synaptic plasticity. In the deprived cortex, homeostatic mechanisms of plasticity regulate synaptic function after prolonged periods of sensory loss, whereas spared cortical areas undergo compensatory cross-modal synaptic plasticity. We have utilized rodent primary visual cortex (V1) to investigate the mechanisms that mediate these compensatory changes after sensory loss. Here, we demonstrate the indispensable role of NMDARs in both types of plasticity. First, we provide evidence for the requirement of NMDARs in homeostatic synaptic plasticity after uni-modal sensory loss (dark exposure). In parallel, we induced cross-modal plasticity in V1 of adult mice by deafening animals older than 3 months (P90-120). Inspired by previous work showing synaptic strengthening in the feedforward thalamic input after cross-modal sensory deprivation (Petrus et al., 2014), we investigated the molecular mechanisms underlying this post- critical period plasticity. We show that cross-modal TC plasticity in the adult brain is driven mainly by the resurgence of NMDAR-dependent LTP at TC synapses, with no modulation on feedforward inhibition. Moreover, we demonstrate in vivo functional consequences of deafening on V1 by using ocular dominance plasticity (ODP) as a model. Briefly, we show that deafening accelerates ODP in adult V1 by promoting open-eye potentiation during monocular deprivation (MD). Taken together, our results indicate that both uni-modal and cross-modal plasticity rely on similar molecular mechanisms to adapt to changes in the environment. They also provide insights into the brain’s ability to adapt beyond the critical period and suggest cross-modal sensory deprivation may be an effective way to re-engage plasticity in the adult brain

Autism: A “Critical Period” Disorder?

Cortical circuits in the brain are refined by experience during critical periods early in postnatal life. Critical periods are regulated by the balance of excitatory and inhibitory (E/I) neurotransmission in the brain during development. There is now increasing evidence of E/I imbalance in autism, a complex genetic neurodevelopmental disorder diagnosed by abnormal socialization, impaired communication, and repetitive behaviors or restricted interests. The underlying cause is still largely unknown and there is no fully effective treatment or cure. We propose that alteration of the expression and/or timing of critical period circuit refinement in primary sensory brain areas may significantly contribute to autistic phenotypes, including cognitive and behavioral impairments. Dissection of the cellular and molecular mechanisms governing well-established critical periods represents a powerful tool to identify new potential therapeutic targets to restore normal plasticity and function in affected neuronal circuits

The thalamocortical symphony:How thalamus and cortex play together in schizophrenia and plasticity

The work presented in this thesis aimed at investigating the function and mechanism of corticothalamic-thalamocortical network in schizophrenia and experience-dependent plasticity, further discussed their possible connection.In Chapter 2, we examined the effects of low-dose ketamine on the corticothalamic circuit (CTC) system. Our findings reveal that ketamine induces abnormal spindle activity and gamma oscillations in the CTC system. Notably, ketamine also leads to a transition in thalamic neurons from burst-firing to tonic action potential mode, which may underlie deficits in spindle oscillations. Chapter 3 addresses sensory perception deficits in schizophrenia, emphasizing disruptions in beta and gamma frequency oscillations due to signal-to-noise ratio imbalances. Chapter 4 explores experience-dependent plasticity, highlighting the role of thalamic synaptic inhibition in ocular dominance plasticity and the influence of cortical feedback. Chapter 5 investigates the involvement of endocannabinoids, particularly CB1 receptors, in inhibitory synaptic maturation and ocular dominance plasticity within the primary visual cortex.The general discussion raises the possibility of a link between neural plasticity and schizophrenia, particularly during the transformative phase of adolescence when the brain undergoes significant changes. An abnormal balance between inhibition and excitation, influenced by GABAergic maturation deficits, connectivity disruptions, and altered perceptual information transfer, may contribute to the development of schizophrenia.This thesis offers valuable insights into the intricate mechanisms underlying schizophrenia, with a particular focus on the CTC circuit, NMDA receptors, and endocannabinoids in the context of neuronal plasticity and cognitive function

The thalamocortical symphony:How thalamus and cortex play together in schizophrenia and plasticity

The work presented in this thesis aimed at investigating the function and mechanism of corticothalamic-thalamocortical network in schizophrenia and experience-dependent plasticity, further discussed their possible connection.In Chapter 2, we examined the effects of low-dose ketamine on the corticothalamic circuit (CTC) system. Our findings reveal that ketamine induces abnormal spindle activity and gamma oscillations in the CTC system. Notably, ketamine also leads to a transition in thalamic neurons from burst-firing to tonic action potential mode, which may underlie deficits in spindle oscillations. Chapter 3 addresses sensory perception deficits in schizophrenia, emphasizing disruptions in beta and gamma frequency oscillations due to signal-to-noise ratio imbalances. Chapter 4 explores experience-dependent plasticity, highlighting the role of thalamic synaptic inhibition in ocular dominance plasticity and the influence of cortical feedback. Chapter 5 investigates the involvement of endocannabinoids, particularly CB1 receptors, in inhibitory synaptic maturation and ocular dominance plasticity within the primary visual cortex.The general discussion raises the possibility of a link between neural plasticity and schizophrenia, particularly during the transformative phase of adolescence when the brain undergoes significant changes. An abnormal balance between inhibition and excitation, influenced by GABAergic maturation deficits, connectivity disruptions, and altered perceptual information transfer, may contribute to the development of schizophrenia.This thesis offers valuable insights into the intricate mechanisms underlying schizophrenia, with a particular focus on the CTC circuit, NMDA receptors, and endocannabinoids in the context of neuronal plasticity and cognitive function

Regulation of circuit organization and function through inhibitory synaptic plasticity

Diverse inhibitory neurons in the mammalian brain shape circuit connectivity and dynamics through mechanisms of synaptic plasticity. Inhibitory plasticity can establish excitation/inhibition (E/I) balance, control neuronal firing, and affect local calcium concentration, hence regulating neuronal activity at the network, single neuron, and dendritic level. Computational models can synthesize multiple experimental results and provide insight into how inhibitory plasticity controls circuit dynamics and sculpts connectivity by identifying phenomenological learning rules amenable to mathematical analysis. We highlight recent studies on the role of inhibitory plasticity in modulating excitatory plasticity, forming structured networks underlying memory formation and recall, and implementing adaptive phenomena and novelty detection. We conclude with experimental and modeling progress on the role of interneuron-specific plasticity in circuit computation and context-dependent learning

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