Pharmacological and optical activation of TrkB in Parvalbumin interneurons regulate intrinsic states to orchestrate cortical plasticity

AbstractElevated states of brain plasticity typical for critical periods of early postnatal life can be reinstated in the adult brain through interventions, such as antidepressant treatment and environmental enrichment, and induced plasticity may be critical for the antidepressant action. Parvalbumin-positive (PV) interneurons regulate the closure of developmental critical periods and can alternate between high and low plasticity states in response to experience in adulthood. We now show that PV plasticity states and cortical networks are regulated through the activation of TrkB neurotrophin receptors. Visual cortical plasticity induced by fluoxetine, a widely prescribed selective serotonin reuptake inhibitor (SSRI) antidepressant, was lost in mice with reduced expression of TrkB in PV interneurons. Conversely, optogenetic gain-of-function studies revealed that activation of an optically activatable TrkB (optoTrkB) specifically in PV interneurons switches adult cortical networks into a state of elevated plasticity within minutes by decreasing the intrinsic excitability of PV interneurons, recapitulating the effects of fluoxetine. TrkB activation shifted cortical networks towards a low PV configuration, promoting oscillatory synchrony, increased excitatory-inhibitory balance, and ocular dominance plasticity. OptoTrkB activation promotes the phosphorylation of Kv3.1 channels and reduces the expression of Kv3.2 mRNA providing a mechanism for the lower excitability. In addition, decreased expression and puncta of Synaptotagmin2 (Syt2), a presynaptic marker of PV interneurons involved in Ca2+-dependent neurotransmitter release, suggests lower inputs onto pyramidal neurons suppressing feed-forward inhibition. Together, the results provide mechanistic insights into how TrkB activation in PV interneurons orchestrates the activity of cortical networks and mediating antidepressant responses in the adult brain.

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Optical TrkB activation in Parvalbumin interneurons regulates intrinsic states to orchestrate cortical plasticity

10.1101/2020.04.27.063503 ◽

2020 ◽

Author(s):

Frederike Winkel ◽

Mathias B. Voigt ◽

Giuliano Didio ◽

Salomé Matéo ◽

Elias Jetsonen ◽

...

Keyword(s):

Gene Expression ◽

Neuronal Plasticity ◽

Cortical Plasticity ◽

Ocular Dominance ◽

Neurotrophin Receptors ◽

Critical Periods ◽

Cortical Networks ◽

Ocular Dominance Plasticity ◽

Visual Plasticity ◽

Parvalbumin Interneurons

AbstractActivation state of Parvalbumin (PV) interneurons regulates neuronal plasticity, driving the closure of developmental critical periods and alternating between high and low plasticity states in response to experience in adulthood. We now show that PV plasticity states are regulated through the activation of TrkB neurotrophin receptors. Activation of an optically activatable TrkB (optoTrkB) specifically in PV interneurons switches adult cortical networks into a state of elevated plasticity within minutes by decreasing excitability of PV neurons. OptoTrkB activation induces changes in gene expression related to neuronal plasticity and excitability, and increases the phosphorylation of Kv3.1 channels. OptoTrkB activation shifted cortical networks towards a low PV configuration, promoting oscillatory synchrony and ocular dominance plasticity. Visual plasticity induced by fluoxetine was lost in mice lacking TrkB in PV neurons. Our data suggest a novel mechanism that dynamically regulates PV interneurons configuration state and orchestrates cortical networks during adulthood.Graphical Abstract

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An Extracellular Perspective on CNS Maturation: Perineuronal Nets and the Control of Plasticity

International Journal of Molecular Sciences ◽

10.3390/ijms22052434 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2434

Author(s):

Daniela Carulli ◽

Joost Verhaagen

Keyword(s):

Critical Period ◽

Brain Plasticity ◽

Time Windows ◽

Adult Brain ◽

Mammalian Brain ◽

Postnatal Life ◽

Perineuronal Nets ◽

Critical Periods ◽

Perineuronal Net ◽

Memory Processes

During restricted time windows of postnatal life, called critical periods, neural circuits are highly plastic and are shaped by environmental stimuli. In several mammalian brain areas, from the cerebral cortex to the hippocampus and amygdala, the closure of the critical period is dependent on the formation of perineuronal nets. Perineuronal nets are a condensed form of an extracellular matrix, which surrounds the soma and proximal dendrites of subsets of neurons, enwrapping synaptic terminals. Experimentally disrupting perineuronal nets in adult animals induces the reactivation of critical period plasticity, pointing to a role of the perineuronal net as a molecular brake on plasticity as the critical period closes. Interestingly, in the adult brain, the expression of perineuronal nets is remarkably dynamic, changing its plasticity-associated conditions, including memory processes. In this review, we aimed to address how perineuronal nets contribute to the maturation of brain circuits and the regulation of adult brain plasticity and memory processes in physiological and pathological conditions.

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Temporal patterns of fluoxetine-induced plasticity in the mouse visual cortex

10.1101/487553 ◽

2018 ◽

Author(s):

Anna Steinzeig ◽

Cecilia Cannarozzo ◽

Eero Castren

Keyword(s):

Visual Cortex ◽

Critical Period ◽

Ocular Dominance ◽

Temporal Patterns ◽

Monocular Deprivation ◽

Adult Brain ◽

Postnatal Life ◽

Critical Periods ◽

Mouse Visual Cortex

Heightened neuronal plasticity expressed during early postnatal life has been thought to permanently decline once critical periods have ended. For example, monocular deprivation is able to shift ocular dominance in the mouse visual cortex during the first months of life, but this effect is lost later in life. However, various treatments such as the antidepressant fluoxetine can reactivate a critical period-like plasticity in the adult brain. When monocular deprivation is supplemented with chronic fluoxetine administration, a major shift in ocular dominance is produced after the critical period has ended. In the current study, we characterized the temporal patterns of fluoxetine-induced plasticity in the adult mouse visual cortex, using in vivo optical imaging. We found that artificially-induced plasticity in ocular dominance extended beyond the duration of the naturally occurring critical period, and continued as long as fluoxetine was administered. However, this fluoxetine-induced plasticity period ended as soon as the drug was not given. Taken together, our data highlights how a combination of pharmacological treatment and environmental change could be used to improve strategies in antidepressant therapy in humans.

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Gene Expression Patterns Underlying the Reinstatement of Plasticity in the Adult Visual System

Neural Plasticity ◽

10.1155/2013/605079 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 11

Author(s):

Ettore Tiraboschi ◽

Ramon Guirado ◽

Dario Greco ◽

Petri Auvinen ◽

Jose Fernando Maya-Vetencourt ◽

...

Keyword(s):

Gene Expression ◽

Visual Cortex ◽

Large Scale ◽

Molecular Mechanisms ◽

Expression Patterns ◽

Monocular Deprivation ◽

Adult Brain ◽

Gene Expression Patterns ◽

Postnatal Life ◽

Critical Periods

The nervous system is highly sensitive to experience during early postnatal life, but this phase of heightened plasticity decreases with age. Recent studies have demonstrated that developmental-like plasticity can be reactivated in the visual cortex of adult animals through environmental or pharmacological manipulations. These findings provide a unique opportunity to study the cellular and molecular mechanisms of adult plasticity. Here we used the monocular deprivation paradigm to investigate large-scale gene expression patterns underlying the reinstatement of plasticity produced by fluoxetine in the adult rat visual cortex. We found changes, confirmed with RT-PCRs, in gene expression in different biological themes, such as chromatin structure remodelling, transcription factors, molecules involved in synaptic plasticity, extracellular matrix, and excitatory and inhibitory neurotransmission. Our findings reveal a key role for several molecules such as the metalloproteases Mmp2 and Mmp9 or the glycoprotein Reelin and open up new insights into the mechanisms underlying the reopening of the critical periods in the adult brain.

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The gut microbiota of environmentally enriched mice regulates visual cortical plasticity

10.1101/2021.07.16.452307 ◽

2021 ◽

Author(s):

Leonardo Lupori ◽

Sara Cornuti ◽

Raffaele M Mazziotti ◽

Elisa Borghi ◽

Emerenziana Ottaviano ◽

...

Keyword(s):

Gut Microbiota ◽

Cortical Plasticity ◽

Brain Plasticity ◽

Ocular Dominance ◽

Standard Condition ◽

Intestinal Bacteria ◽

Short Chain Fatty Acids ◽

The Body ◽

Antibiotic Cocktail ◽

Visual Cortical

Exposing animals to an enriched environment (EE) has dramatic effects on brain structure, function and plasticity. The poorly known "EE derived signals" mediating the EE effects are thought to be generated within the central nervous system. Here, we shift the focus to the body periphery, revealing that gut microbiota signals are crucial for EE-driven plasticity. Developmental analysis of intestinal bacteria composition in EE mice revealed striking differences from standard condition (ST) animals and enhanced levels of short-chain fatty acids (SCFA). Depleting the EE mice gut microbiota with an antibiotic cocktail decreased SCFA and prevented EE induction of adult ocular dominance (OD) plasticity, spine dynamics and microglia rearrangement. SCFA treatment in ST mice mimicked the EE induction of adult OD plasticity and morphological microglial rearrangement. Remarkably, transferring the microbiota of EE mice to ST recipients activated adult OD plasticity. Thus, taken together our data suggest that experience-dependent changes in gut microbiota regulate brain plasticity.

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Synapse-selective control of cortical maturation and plasticity engages an interneuron-autonomous synaptic switch

10.1101/382614 ◽

2018 ◽

Author(s):

Adema Ribic ◽

Michael C. Crair ◽

Thomas Biederer

Keyword(s):

Visual Cortex ◽

Critical Period ◽

Visual Experience ◽

Cortical Plasticity ◽

Brain Plasticity ◽

Cortical Inhibition ◽

Specific Cell ◽

List Type ◽

Critical Periods ◽

Age Related

HighlightsThe synaptogenic molecule SynCAM 1 is selectively regulated by visual experienceSynCAM 1 controls thalamic input onto cortical Parvalbumin (PV+) interneuronsPV+-specific knockdown of SynCAM 1 arrests maturation of cortical inhibitionThalamic excitation onto PV+ interneurons is essential for critical period closureeTOC BlurbRibic et al. show that network plasticity in both young and adult cortex is restricted by the synapse organizing molecule SynCAM 1. On a cellular level, it functions in Parvalbumin-positive interneurons to recruit thalamocortical terminals. This controls the maturation of inhibitory drive and restricts plasticity in the cortex. These results reveal the synaptic locus of cortical plasticity and identify the first cell-autonomous synaptic factor for closure of cortical critical periods.SummaryBrain plasticity peaks early in life and tapers in adulthood. This is exemplified in the primary visual cortex, where brief loss of vision to one eye abrogates cortical responses to inputs from that eye during the critical period, but not in adulthood. The synaptic locus of critical period plasticity and the cell-autonomous synaptic factors timing these periods remain unclear. We here demonstrate that the immunoglobulin protein Synaptic Cell Adhesion Molecule 1 (SynCAM 1/Cadm1) is regulated by visual experience and limits visual cortex plasticity. SynCAM 1 selectively controls the number of excitatory thalamocortical (TC) inputs onto Parvalbumin (PV+) interneurons and loss of SynCAM 1 in turn impairs the maturation of TC-driven feed-forward inhibition. SynCAM 1 acts in cortical PV+ interneurons to perform these functions and its PV+-specific knockdown prevents the age-related plasticity decline. These results identify a synapse type-specific, cell-autonomous mechanism that governs circuit maturation and closes the visual critical period.

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MEF2C and HDAC5 regulate Egr1 and Arc genes to increase dendritic spine density and complexity in early enriched environment

Neuronal Signaling ◽

10.1042/ns20190147 ◽

2020 ◽

Vol 4 (3) ◽

Author(s):

Shu Juan Puang ◽

Bavani Elanggovan ◽

Tendy Ching ◽

Judy C.G. Sng

Keyword(s):

Transcription Factor ◽

Dendritic Spine ◽

Critical Period ◽

Environmental Enrichment ◽

Cortical Plasticity ◽

Postnatal Life ◽

Spine Density ◽

Dendritic Spine Density ◽

Visual Cortical ◽

Dendritic Complexity

Abstract We investigated the effects of environmental enrichment during critical period of early postnatal life and how it interplays with the epigenome to affect experience-dependent visual cortical plasticity. Mice raised in an EE from birth to during CP have increased spine density and dendritic complexity in the visual cortex. EE upregulates synaptic plasticity genes, Arc and Egr1, and a transcription factor MEF2C. We also observed an increase in MEF2C binding to the promoters of Arc and Egr1. In addition, pups raised in EE show a reduction in HDAC5 and its binding to promoters of Mef2c, Arc and Egr1 genes. With an overexpression of Mef2c, neurite outgrowth increased in complexity. Our results suggest a possible underlying molecular mechanism of EE, acting through MEF2C and HDAC5, which drive Arc and Egr1. This could lead to the observed increased dendritic spine density and complexity induced by early EE.

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Environment and Brain Plasticity: Towards an Endogenous Pharmacotherapy

Physiological Reviews ◽

10.1152/physrev.00036.2012 ◽

2014 ◽

Vol 94 (1) ◽

pp. 189-234 ◽

Cited By ~ 172

Author(s):

Alessandro Sale ◽

Nicoletta Berardi ◽

Lamberto Maffei

Keyword(s):

Environmental Enrichment ◽

Molecular Mechanisms ◽

Brain Plasticity ◽

System Development ◽

Basic Research ◽

Nervous System Development ◽

Adult Brain ◽

Aging Brain ◽

Cerebral Neurons ◽

And Function

Brain plasticity refers to the remarkable property of cerebral neurons to change their structure and function in response to experience, a fundamental theoretical theme in the field of basic research and a major focus for neural rehabilitation following brain disease. While much of the early work on this topic was based on deprivation approaches relying on sensory experience reduction procedures, major advances have been recently obtained using the conceptually opposite paradigm of environmental enrichment, whereby an enhanced stimulation is provided at multiple cognitive, sensory, social, and motor levels. In this survey, we aim to review past and recent work concerning the influence exerted by the environment on brain plasticity processes, with special emphasis on the underlying cellular and molecular mechanisms and starting from experimental work on animal models to move to highly relevant work performed in humans. We will initiate introducing the concept of brain plasticity and describing classic paradigmatic examples to illustrate how changes at the level of neuronal properties can ultimately affect and direct key perceptual and behavioral outputs. Then, we describe the remarkable effects elicited by early stressful conditions, maternal care, and preweaning enrichment on central nervous system development, with a separate section focusing on neurodevelopmental disorders. A specific section is dedicated to the striking ability of environmental enrichment and physical exercise to empower adult brain plasticity. Finally, we analyze in the last section the ever-increasing available knowledge on the effects elicited by enriched living conditions on physiological and pathological aging brain processes.

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The Function of Activity-Regulated Genes in the Nervous System

Physiological Reviews ◽

10.1152/physrev.00013.2009 ◽

2009 ◽

Vol 89 (4) ◽

pp. 1079-1103 ◽

Cited By ~ 136

Author(s):

Sven Loebrich ◽

Elly Nedivi

Keyword(s):

Transcriptional Control ◽

Brain Plasticity ◽

Neuronal Morphology ◽

Adult Brain ◽

Mammalian Brain ◽

Current View ◽

Control Mechanisms ◽

Critical Periods ◽

Cellular Functions ◽

Dynamic Tuning

The mammalian brain is plastic in the sense that it shows a remarkable capacity for change throughout life. The contribution of neuronal activity to brain plasticity was first recognized in relation to critical periods of development, when manipulating the sensory environment was found to profoundly affect neuronal morphology and receptive field properties. Since then, a growing body of evidence has established that brain plasticity extends beyond development and is an inherent feature of adult brain function, spanning multiple domains, from learning and memory to adaptability of primary sensory maps. Here we discuss evolution of the current view that plasticity of the adult brain derives from dynamic tuning of transcriptional control mechanisms at the neuronal level, in response to external and internal stimuli. We then review the identification of “plasticity genes” regulated by changes in the levels of electrical activity, and how elucidating their cellular functions has revealed the intimate role transcriptional regulation plays in fundamental aspects of synaptic transmission and circuit plasticity that occur in the brain on an every day basis.

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The Current Status of Somatostatin-Interneurons in Inhibitory Control of Brain Function and Plasticity

Neural Plasticity ◽

10.1155/2016/8723623 ◽

2016 ◽

Vol 2016 ◽

pp. 1-20 ◽

Cited By ~ 21

Author(s):

Isabelle Scheyltjens ◽

Lutgarde Arckens

Keyword(s):

Cortical Plasticity ◽

Brain Plasticity ◽

Ocular Dominance ◽

Sensory Information ◽

Sensory Function ◽

Sensory Loss ◽

Current Status ◽

Normal Brain ◽

Ocular Dominance Plasticity ◽

Dependent Plasticity

The mammalian neocortex contains many distinct inhibitory neuronal populations to balance excitatory neurotransmission. A correct excitation/inhibition equilibrium is crucial for normal brain development, functioning, and controlling lifelong cortical plasticity. Knowledge about how the inhibitory network contributes to brain plasticity however remains incomplete. Somatostatin- (SST-) interneurons constitute a large neocortical subpopulation of interneurons, next to parvalbumin- (PV-) and vasoactive intestinal peptide- (VIP-) interneurons. Unlike the extensively studied PV-interneurons, acknowledged as key components in guiding ocular dominance plasticity, the contribution of SST-interneurons is less understood. Nevertheless, SST-interneurons are ideally situated within cortical networks to integrate unimodal or cross-modal sensory information processing and therefore likely to be important mediators of experience-dependent plasticity. The lack of knowledge on SST-interneurons partially relates to the wide variety of distinct subpopulations present in the sensory neocortex. This review informs on those SST-subpopulations hitherto described based on anatomical, molecular, or electrophysiological characteristics and whose functional roles can be attributed based on specific cortical wiring patterns. A possible role for these subpopulations in experience-dependent plasticity will be discussed, emphasizing on learning-induced plasticity and on unimodal and cross-modal plasticity upon sensory loss. This knowledge will ultimately contribute to guide brain plasticity into well-defined directions to restore sensory function and promote lifelong learning.

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