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1.
Sci Rep ; 14(1): 20463, 2024 09 03.
Artículo en Inglés | MEDLINE | ID: mdl-39242672

RESUMEN

Sensory experiences and learning induce long-lasting changes in both excitatory and inhibitory synapses, thereby providing a crucial substrate for memory. However, the co-tuning of excitatory long-term potentiation (eLTP) or depression (eLTD) with the simultaneous changes at inhibitory synapses (iLTP/iLTD) remains unclear. Herein, we investigated the co-expression of NMDA-induced synaptic plasticity at excitatory and inhibitory synapses in hippocampal CA1 pyramidal cells (PCs) using a combination of electrophysiological, optogenetic, and pharmacological approaches. We found that inhibitory inputs from somatostatin (SST) and parvalbumin (PV)-positive interneurons onto CA1 PCs display input-specific long-term plastic changes following transient NMDA receptor activation. Notably, synapses from SST-positive interneurons consistently exhibited iLTP, irrespective of the direction of excitatory plasticity, whereas synapses from PV-positive interneurons predominantly showed iLTP concurrent with eLTP, rather than eLTD. As neuroplasticity is known to depend on the extracellular matrix, we tested the impact of metalloproteinases (MMP) inhibition. MMP3 blockade interfered with GABAergic plasticity for all inhibitory inputs, whereas MMP9 inhibition selectively blocked eLTP and iLTP in SST-CA1PC synapses co-occurring with eLTP but not eLTD. These findings demonstrate the dissociation of excitatory and inhibitory plasticity co-expression. We propose that these mechanisms of plasticity co-expression may be involved in maintaining excitation-inhibition balance and modulating neuronal integration modes.


Asunto(s)
Interneuronas , Plasticidad Neuronal , Células Piramidales , Animales , Plasticidad Neuronal/fisiología , Interneuronas/metabolismo , Células Piramidales/metabolismo , Células Piramidales/fisiología , N-Metilaspartato/metabolismo , N-Metilaspartato/farmacología , Hipocampo/metabolismo , Hipocampo/fisiología , Parvalbúminas/metabolismo , Masculino , Ratones , Somatostatina/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapsis/metabolismo , Sinapsis/fisiología , Potenciación a Largo Plazo , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/efectos de los fármacos , Región CA1 Hipocampal/metabolismo , Región CA1 Hipocampal/fisiología , Metaloproteinasa 9 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/genética
2.
J Neurosci ; 43(13): 2305-2325, 2023 03 29.
Artículo en Inglés | MEDLINE | ID: mdl-36813575

RESUMEN

Cholecystokinin (CCK) enables excitatory circuit long-term potentiation (LTP). Here, we investigated its involvement in the enhancement of inhibitory synapses. Activation of GABA neurons suppressed neuronal responses in the neocortex to a forthcoming auditory stimulus in mice of both sexes. High-frequency laser stimulation (HFLS) of GABAergic neurons potentiated this suppression. HFLS of CCK interneurons could induce the LTP of their inhibition toward pyramidal neurons. This potentiation was abolished in CCK knock-out mice but intact in mice with both CCK1R and 2R knockout of both sexes. Next, we combined bioinformatics analysis, multiple unbiased cell-based assays, and histology examinations to identify a novel CCK receptor, GPR173. We propose GPR173 as CCK3R, which mediates the relationship between cortical CCK interneuron signaling and inhibitory LTP in the mice of either sex. Thus, GPR173 might represent a promising therapeutic target for brain disorders related to excitation and inhibition imbalance in the cortex.SIGNIFICANCE STATEMENT CCK, the most abundant and widely distributed neuropeptide in the CNS, colocalizes with many neurotransmitters and modulators. GABA is one of the important inhibitory neurotransmitters, and much evidence shows that CCK may be involved in modulating GABA signaling in many brain areas. However, the role of CCK-GABA neurons in the cortical microcircuits is still unclear. We identified a novel CCK receptor, GPR173, localized in the CCK-GABA synapses and mediated the enhancement of the GABA inhibition effect, which might represent a promising therapeutic target for brain disorders related to excitation and inhibition imbalance in the cortex.


Asunto(s)
GABAérgicos , Receptores de Colecistoquinina , Masculino , Femenino , Ratones , Animales , GABAérgicos/farmacología , Células Piramidales/fisiología , Sinapsis/fisiología , Neuronas GABAérgicas/fisiología , Ratones Noqueados , Interneuronas , Colecistoquinina , Ácido gamma-Aminobutírico/fisiología , Potenciación a Largo Plazo/fisiología , Receptores Acoplados a Proteínas G/genética
3.
J Neurosci ; 42(42): 7921-7930, 2022 10 19.
Artículo en Inglés | MEDLINE | ID: mdl-36261269

RESUMEN

Sensory loss leads to widespread cross-modal plasticity across brain areas to allow the remaining senses to guide behavior. While multimodal sensory interactions are often attributed to higher-order sensory areas, cross-modal plasticity has been observed at the level of synaptic changes even across primary sensory cortices. In particular, vision loss leads to widespread circuit adaptation in the primary auditory cortex (A1) even in adults. Here we report using mice of both sexes in which cross-modal plasticity occurs even earlier in the sensory-processing pathway at the level of the thalamus in a modality-selective manner. A week of visual deprivation reduced inhibitory synaptic transmission from the thalamic reticular nucleus (TRN) to the primary auditory thalamus (MGBv) without changes to the primary visual thalamus (dLGN). The plasticity of TRN inhibition to MGBv was observed as a reduction in postsynaptic gain and short-term depression. There was no observable plasticity of the cortical feedback excitatory synaptic transmission from the primary visual cortex to dLGN or TRN and A1 to MGBv, which suggests that the visual deprivation-induced plasticity occurs predominantly at the level of thalamic inhibition. We provide evidence that visual deprivation-induced change in the short-term depression of TRN inhibition to MGBv involves endocannabinoid CB1 receptors. TRN inhibition is considered critical for sensory gating, selective attention, and multimodal performances; hence, its plasticity has implications for sensory processing. Our results suggest that selective disinhibition and altered short-term dynamics of TRN inhibition in the spared thalamic nucleus support cross-modal plasticity in the adult brain.SIGNIFICANCE STATEMENT Losing vision triggers adaptation of the brain to enhance the processing of the remaining senses, which can be observed as better auditory performance in blind subjects. We previously found that depriving vision of adult rodents produces widespread circuit reorganization in the primary auditory cortex and enhances auditory processing at a neural level. Here we report that visual deprivation-induced plasticity in adults occurs much earlier in the auditory pathway, at the level of thalamic inhibition. Sensory processing is largely gated at the level of the thalamus via strong cortical feedback inhibition mediated through the thalamic reticular nucleus (TRN). We found that TRN inhibition of the auditory thalamus is selectively reduced by visual deprivation, thus playing a role in adult cross-modal plasticity.


Asunto(s)
Endocannabinoides , Núcleos Talámicos , Masculino , Femenino , Ratones , Animales , Núcleos Talámicos/fisiología , Tálamo/fisiología , Vías Auditivas/fisiología , Transmisión Sináptica/fisiología
4.
Neuron ; 110(20): 3302-3317.e7, 2022 10 19.
Artículo en Inglés | MEDLINE | ID: mdl-36070750

RESUMEN

Homeostatic plasticity (HP) encompasses a suite of compensatory physiological processes that counteract neuronal perturbations, enabling brain resilience. Currently, we lack a complete description of the homeostatic processes that operate within the mammalian brain. Here, we demonstrate that acute, partial AMPAR-specific antagonism induces potentiation of presynaptic neurotransmitter release in adult hippocampus, a form of compensatory plasticity that is consistent with the expression of presynaptic homeostatic plasticity (PHP) documented at peripheral synapses. We show that this compensatory plasticity can be induced within minutes, requires postsynaptic NMDARs, and is expressed via correlated increases in dendritic spine volume, active zone area, and docked vesicle number. Further, simultaneous postsynaptic genetic reduction of GluA1, GluA2, and GluA3 in triple heterozygous knockouts induces potentiation of presynaptic release. Finally, induction of compensatory plasticity at excitatory synapses induces a parallel, NMDAR-dependent potentiation of inhibitory transmission, a cross-modal effect consistent with the anti-epileptic activity of AMPAR-specific antagonists used in humans.


Asunto(s)
Receptores de N-Metil-D-Aspartato , Sinapsis , Humanos , Animales , Sinapsis/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Hipocampo/fisiología , Homeostasis/fisiología , Neurotransmisores/metabolismo , Plasticidad Neuronal/fisiología , Mamíferos/metabolismo
5.
Elife ; 102021 10 14.
Artículo en Inglés | MEDLINE | ID: mdl-34647889

RESUMEN

Animals depend on fast and reliable detection of novel stimuli in their environment. Neurons in multiple sensory areas respond more strongly to novel in comparison to familiar stimuli. Yet, it remains unclear which circuit, cellular, and synaptic mechanisms underlie those responses. Here, we show that spike-timing-dependent plasticity of inhibitory-to-excitatory synapses generates novelty responses in a recurrent spiking network model. Inhibitory plasticity increases the inhibition onto excitatory neurons tuned to familiar stimuli, while inhibition for novel stimuli remains low, leading to a network novelty response. The generation of novelty responses does not depend on the periodicity but rather on the distribution of presented stimuli. By including tuning of inhibitory neurons, the network further captures stimulus-specific adaptation. Finally, we suggest that disinhibition can control the amplification of novelty responses. Therefore, inhibitory plasticity provides a flexible, biologically plausible mechanism to detect the novelty of bottom-up stimuli, enabling us to make experimentally testable predictions.


Asunto(s)
Conducta Animal , Corteza Cerebral/fisiología , Conducta Exploratoria , Modelos Neurológicos , Inhibición Neural , Plasticidad Neuronal , Transmisión Sináptica , Potenciales de Acción , Animales , Simulación por Computador , Ratones , Periodicidad , Tiempo de Reacción , Detección de Señal Psicológica , Factores de Tiempo
6.
FASEB J ; 35(10): e21944, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34569087

RESUMEN

Information represented by principal neurons in anterior piriform cortex (APC) is regulated by local, recurrent excitation and inhibition, but the circuit mechanisms remain elusive. Two types of layer 2 (L2) principal neurons, semilunar (SL), and superficial pyramidal (SP) cells, are parallel output channels, and the control of their activity gates the output of APC. Here, we examined the hypothesis that recurrent inhibition differentially regulates SL and SP cells. Patterned optogenetic stimulation revealed that the strength of recurrent inhibition is target- and layer-specific: L1 > L3 for SL cells, but L3 > L1 for SP cells. This target- and layer-specific inhibition was largely attributable to the parvalbumin (PV), but not somatostatin, interneurons. Intriguingly, olfactory experience selectively modulated the PV to SP microcircuit while maintaining the overall target and laminar specificity of inhibition. Together, these results indicate the importance of target-specific inhibitory wiring for odor processing, implicating these mechanisms in gating the output of piriform cortex.


Asunto(s)
Inhibición Neural , Vías Nerviosas , Corteza Piriforme/citología , Corteza Piriforme/metabolismo , Animales , Femenino , Interneuronas/metabolismo , Masculino , Ratones , Nariz , Odorantes/análisis , Percepción Olfatoria/fisiología , Parvalbúminas/metabolismo , Olfato/fisiología , Somatostatina , Transmisión Sináptica
7.
Cell Rep ; 36(8): 109577, 2021 08 24.
Artículo en Inglés | MEDLINE | ID: mdl-34433026

RESUMEN

Despite ongoing experiential change, neural activity maintains remarkable stability. Although this is thought to be mediated by homeostatic plasticity, what aspect of neural activity is conserved and how the flexibility necessary for learning and memory is maintained is not fully understood. Experimental studies suggest that there exists network-centered, in addition to the well-studied neuron-centered, control. Here we computationally study such a potential mechanism: input-dependent inhibitory plasticity (IDIP). In a hippocampal model, we show that IDIP can explain the emergence of active and silent place cells as well as remapping following silencing of active place cells. Furthermore, we show that IDIP can also stabilize recurrent dynamics while preserving firing rate heterogeneity and stimulus representation, as well as persistent activity after memory encoding. Hence, the establishment of global network balance with IDIP has diverse functional implications and may be able to explain experimental phenomena across different brain areas.


Asunto(s)
Región CA1 Hipocampal/fisiología , Homeostasis/fisiología , Modelos Neurológicos , Red Nerviosa/fisiología , Plasticidad Neuronal/fisiología , Neuronas/fisiología , Animales , Humanos
8.
Neural Netw ; 131: 37-49, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-32750603

RESUMEN

Cortical neurons are silent most of the time: sparse activity enables low-energy computation in the brain, and promises to do the same in neuromorphic hardware. Beyond power efficiency, sparse codes have favourable properties for associative learning, as they can store more information than local codes but are easier to read out than dense codes. Auto-encoders with a sparse constraint can learn sparse codes, and so can single-layer networks that combine recurrent inhibition with unsupervised Hebbian learning. But the latter usually require fast homeostatic plasticity, which could lead to catastrophic forgetting in embodied agents that learn continuously. Here we set out to explore whether plasticity at recurrent inhibitory synapses could take up that role instead, regulating both the population sparseness and the firing rates of individual neurons. We put the idea to the test in a network that employs compartmentalised inputs to solve the task: rate-based dendritic compartments integrate the feedforward input, while spiking integrate-and-fire somas compete through recurrent inhibition. A somato-dendritic learning rule allows somatic inhibition to modulate nonlinear Hebbian learning in the dendrites. Trained on MNIST digits and natural images, the network discovers independent components that form a sparse encoding of the input and support linear decoding. These findings confirm that intrinsic homeostatic plasticity is not strictly required for regulating sparseness: inhibitory synaptic plasticity can have the same effect. Our work illustrates the usefulness of compartmentalised inputs, and makes the case for moving beyond point neuron models in artificial spiking neural networks.


Asunto(s)
Aprendizaje Automático , Redes Neurales de la Computación , Plasticidad Neuronal , Aprendizaje por Asociación , Dendritas/fisiología , Retroalimentación , Humanos
9.
J Neurosci ; 39(23): 4475-4488, 2019 06 05.
Artículo en Inglés | MEDLINE | ID: mdl-30940716

RESUMEN

During a critical period in development, spontaneous and evoked retinal activity shape visual pathways in an adaptive fashion. Interestingly, spontaneous activity is sufficient for spatial refinement of visual receptive fields (RFs) in superior colliculus (SC) and visual cortex (V1), but early visual experience is necessary to maintain inhibitory synapses and stabilize RFs in adulthood (Carrasco et al., 2005, 2011; Carrasco and Pallas, 2006; Balmer and Pallas, 2015a). In V1, BDNF and its high-affinity receptor TrkB are important for development of visual acuity, inhibition, and regulation of the critical period for ocular dominance plasticity (Hanover et al., 1999; Huang et al., 1999; Gianfranceschi et al., 2003). To examine the generality of this signaling pathway for visual system plasticity, the present study examined the role of TrkB signaling during the critical period for RF refinement in SC. Activating TrkB receptors during the critical period (P33-P40) in dark reared subjects produced normally refined RFs, and blocking TrkB receptors in light-exposed animals resulted in enlarged adult RFs like those in dark reared animals. We also report here that deprivation- or TrkB blockade-induced RF enlargement in adulthood impaired fear responses to looming overhead stimuli and negatively impacted visual acuity. Thus, early TrkB activation is both necessary and sufficient to maintain visual RF refinement, robust looming responses, and visual acuity in adulthood. These findings suggest a common signaling pathway exists for the maturation of inhibition between V1 and SC.SIGNIFICANCE STATEMENT Receptive field refinement in superior colliculus differs from more commonly studied examples of critical period plasticity in visual pathways in that it does not require visual experience to occur; rather, spontaneous activity is sufficient. Maintenance of refinement beyond puberty requires a brief, early exposure to light to stabilize the lateral inhibition that shapes receptive fields. We find that TrkB activation during a critical period can substitute for visual experience in maintaining receptive field refinement into adulthood, and that this maintenance is beneficial to visual survival behaviors. Thus, as in some other types of plasticity, TrkB signaling plays a crucial role in receptive field refinement.


Asunto(s)
Envejecimiento/fisiología , Glicoproteínas de Membrana/fisiología , Proteínas Tirosina Quinasas/fisiología , Privación Sensorial/fisiología , Colículos Superiores/fisiología , Percepción Visual/fisiología , Animales , Azepinas/farmacología , Benzamidas/farmacología , Cricetinae , Período Crítico Psicológico , Oscuridad , Miedo/fisiología , Femenino , Flavonas/farmacología , Masculino , Aprendizaje por Laberinto , Glicoproteínas de Membrana/agonistas , Glicoproteínas de Membrana/antagonistas & inhibidores , Mesocricetus , Ratones , Ratones Endogámicos C57BL , Fosforilación , Estimulación Luminosa , Procesamiento Proteico-Postraduccional , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Colículos Superiores/efectos de los fármacos , Colículos Superiores/crecimiento & desarrollo , Percepción Visual/efectos de la radiación
10.
Neuron ; 96(1): 177-189.e7, 2017 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-28957667

RESUMEN

Long-term modifications of neuronal connections are critical for reliable memory storage in the brain. However, their locus of expression-pre- or postsynaptic-is highly variable. Here we introduce a theoretical framework in which long-term plasticity performs an optimization of the postsynaptic response statistics toward a given mean with minimal variance. Consequently, the state of the synapse at the time of plasticity induction determines the ratio of pre- and postsynaptic modifications. Our theory explains the experimentally observed expression loci of the hippocampal and neocortical synaptic potentiation studies we examined. Moreover, the theory predicts presynaptic expression of long-term depression, consistent with experimental observations. At inhibitory synapses, the theory suggests a statistically efficient excitatory-inhibitory balance in which changes in inhibitory postsynaptic response statistics specifically target the mean excitation. Our results provide a unifying theory for understanding the expression mechanisms and functions of long-term synaptic transmission plasticity.


Asunto(s)
Modelos Neurológicos , Plasticidad Neuronal/fisiología , Transmisión Sináptica/fisiología , Animales , Hipocampo/fisiología , Potenciación a Largo Plazo/fisiología , Depresión Sináptica a Largo Plazo/fisiología , Neocórtex/fisiología , Inhibición Neural/fisiología
11.
Front Neurosci ; 11: 344, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28701910

RESUMEN

Evolution and development are interdependent, particularly with regard to the construction of the nervous system and its position as the machine that produces behavior. On the one hand, the processes directing development and plasticity of the brain provide avenues through which natural selection can sculpt neural cell fate and connectivity, and on the other hand, they are themselves subject to selection pressure. For example, mutations that produce heritable perturbations in neuronal birth and death rates, transcription factor expression, or availability of axon guidance factors within sensory pathways can markedly affect the development of form and thus the function of stimulus decoding circuitry. This evolvability of flexible circuits makes them more adaptable to environmental variation. Although there is general agreement on this point, whether the sensitivity of circuits to environmental influence and the mechanisms underlying development and plasticity of sensory pathways are similar across species from different ecological niches has received almost no attention. Neural circuits are generally more sensitive to environmental influences during an early critical period, but not all niches afford the same access to stimuli in early life. Furthermore, depending on predictability of the habitat and ecological niche, sensory coding circuits might be more susceptible to sensory experience in some species than in others. Despite decades of work on understanding the mechanisms underlying critical period plasticity, the importance of ecological niche in visual pathway development has received little attention. Here, I will explore the relationship between critical period plasticity and ecological niche in mammalian sensory pathways.

12.
Proc Natl Acad Sci U S A ; 114(26): 6666-6674, 2017 06 27.
Artículo en Inglés | MEDLINE | ID: mdl-28611219

RESUMEN

Nervous systems use excitatory cell assemblies to encode and represent sensory percepts. Similarly, synaptically connected cell assemblies or "engrams" are thought to represent memories of past experience. Multiple lines of recent evidence indicate that brain systems create and use inhibitory replicas of excitatory representations for important cognitive functions. Such matched "inhibitory engrams" can form through homeostatic potentiation of inhibition onto postsynaptic cells that show increased levels of excitation. Inhibitory engrams can reduce behavioral responses to familiar stimuli, thereby resulting in behavioral habituation. In addition, by preventing inappropriate activation of excitatory memory engrams, inhibitory engrams can make memories quiescent, stored in a latent form that is available for context-relevant activation. In neural networks with balanced excitatory and inhibitory engrams, the release of innate responses and recall of associative memories can occur through focused disinhibition. Understanding mechanisms that regulate the formation and expression of inhibitory engrams in vivo may help not only to explain key features of cognition but also to provide insight into transdiagnostic traits associated with psychiatric conditions such as autism, schizophrenia, and posttraumatic stress disorder.


Asunto(s)
Trastorno Autístico/fisiopatología , Memoria , Modelos Neurológicos , Red Nerviosa/fisiopatología , Percepción , Esquizofrenia/fisiopatología , Trastornos por Estrés Postraumático/fisiopatología , Animales , Cognición , Humanos
13.
Proc Natl Acad Sci U S A ; 113(35): 9898-903, 2016 08 30.
Artículo en Inglés | MEDLINE | ID: mdl-27531957

RESUMEN

Dynamic changes of the strength of inhibitory synapses play a crucial role in processing neural information and in balancing network activity. Here, we report that the efficacy of GABAergic connections between Golgi cells and granule cells in the cerebellum is persistently altered by the activity of glutamatergic synapses. This form of plasticity is heterosynaptic and is expressed as an increase (long-term potentiation, LTPGABA) or a decrease (long-term depression, LTDGABA) of neurotransmitter release. LTPGABA is induced by postsynaptic NMDA receptor activation, leading to calcium increase and retrograde diffusion of nitric oxide, whereas LTDGABA depends on presynaptic NMDA receptor opening. The sign of plasticity is determined by the activation state of target granule and Golgi cells during the induction processes. By controlling the timing of spikes emitted by granule cells, this form of bidirectional plasticity provides a dynamic control of the granular layer encoding capacity.


Asunto(s)
Neuronas GABAérgicas/fisiología , Plasticidad Neuronal/fisiología , Sinapsis/fisiología , Transmisión Sináptica/fisiología , Animales , Calcio/metabolismo , Cerebelo/citología , Cerebelo/fisiología , Neuronas GABAérgicas/metabolismo , Potenciales Postsinápticos Inhibidores/fisiología , Potenciación a Largo Plazo , Depresión Sináptica a Largo Plazo , Microscopía Confocal , Neuronas/metabolismo , Neuronas/fisiología , Óxido Nítrico/metabolismo , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo
14.
Neurobiol Learn Mem ; 127: 10-6, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26593151

RESUMEN

The lateral/basolateral amygdala (BLA) is crucial to the acquisition and extinction of Pavlovian fear conditioning, and synaptic plasticity in this region is considered to be a neural correlate of learned fear. We recently reported that activation of BLA ß3-adrenoreceptors (ß3-ARs) selectively enhances lateral paracapsular (LPC) feed-forward GABAergic inhibition onto BLA pyramidal neurons, and that intra-BLA infusion of a ß3-AR agonist reduces measures of unconditioned anxiety-like behavior. Here, we utilized a combination of behavioral and electrophysiological approaches to characterize the role of BLA LPCs in the acquisition of fear and extinction learning in adult male Long-Evans rats. We report that intra-BLA microinjection of ß3-AR agonists (BRL37344 or SR58611A, 1µg/0.5µL/side) prior to training fear conditioning or extinction blocks the expression of these behaviors 24h later. Furthermore,ex vivo low-frequency stimulation of the external capsule (LFS; 1Hz, 15min), which engages LPC synapses, induces LTP of BLA fEPSPs, while application of a ß3-AR agonist (SR58611A, 5µM) induces LTD of fEPSPs when combined with LFS. Interestingly, fEPSP LTP is not observed in recordings from fear conditioned animals, suggesting that fear learning may engage the same mechanisms that induce synaptic plasticity at this input. In support of this, we find that LFS produces LTD of inhibitory postsynaptic currents (iLTD) at LPC GABAergic synapses, and that this effect is also absent following fear conditioning. Taken together, these data provide preliminary evidence that modulation of LPC GABAergic synapses can influence the acquisition and extinction of fear learning and related synaptic plasticity in the BLA.


Asunto(s)
Complejo Nuclear Basolateral/fisiología , Condicionamiento Clásico/fisiología , Extinción Psicológica/fisiología , Miedo/fisiología , Neuronas GABAérgicas/fisiología , Células Piramidales/fisiología , Agonistas Adrenérgicos beta/administración & dosificación , Animales , Complejo Nuclear Basolateral/efectos de los fármacos , Condicionamiento Clásico/efectos de los fármacos , Estimulación Eléctrica , Etanolaminas/administración & dosificación , Cápsula Externa/fisiología , Extinción Psicológica/efectos de los fármacos , Miedo/efectos de los fármacos , Neuronas GABAérgicas/efectos de los fármacos , Masculino , Plasticidad Neuronal/efectos de los fármacos , Células Piramidales/efectos de los fármacos , Ratas , Ratas Long-Evans , Reflejo de Sobresalto/efectos de los fármacos , Potenciales Sinápticos , Tetrahidronaftalenos/administración & dosificación
15.
J Neurophysiol ; 115(3): 1170-82, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26655825

RESUMEN

During development GABA and glycine synapses are initially excitatory before they gradually become inhibitory. This transition is due to a developmental increase in the activity of neuronal potassium-chloride cotransporter 2 (KCC2), which shifts the chloride equilibrium potential (ECl) to values more negative than the resting membrane potential. While the role of early GABA and glycine depolarizations in neuronal development has become increasingly clear, the role of the transition to hyperpolarization in synapse maturation and circuit refinement has remained an open question. Here we investigated this question by examining the maturation and developmental refinement of GABA/glycinergic and glutamatergic synapses in the lateral superior olive (LSO), a binaural auditory brain stem nucleus, in KCC2-knockdown mice, in which GABA and glycine remain depolarizing. We found that many key events in the development of synaptic inputs to the LSO, such as changes in neurotransmitter phenotype, strengthening and elimination of GABA/glycinergic connection, and maturation of glutamatergic synapses, occur undisturbed in KCC2-knockdown mice compared with wild-type mice. These results indicate that maturation of inhibitory and excitatory synapses in the LSO is independent of the GABA and glycine depolarization-to-hyperpolarization transition.


Asunto(s)
Glicina/metabolismo , Potenciales de la Membrana , Neurogénesis , Complejo Olivar Superior/fisiología , Sinapsis/fisiología , Ácido gamma-Aminobutírico/metabolismo , Animales , Neuronas GABAérgicas/citología , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/fisiología , Ratones , Complejo Olivar Superior/citología , Complejo Olivar Superior/crecimiento & desarrollo , Complejo Olivar Superior/metabolismo , Simportadores/genética , Simportadores/metabolismo , Sinapsis/metabolismo , Cotransportadores de K Cl
17.
Front Cell Neurosci ; 9: 262, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26217186
18.
J Neurophysiol ; 113(7): 2049-61, 2015 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-25568162

RESUMEN

Progressive loss of plasticity during development prevents refined circuits from regressing to an immature state and is thought to depend on maturation of GABAergic inhibition. For example, a gradual reduction in size of visual receptive fields (RFs) occurs in the superior colliculus (SC) during development. Maintenance of the refined state throughout adulthood requires early light exposure. Here we investigate the potential role of changes in long- or short-term plasticity in experience-dependent maintenance of refined RFs. Using an acute SC slice preparation, we found that long-term plasticity was not affected by visual deprivation, indicating that it does not underlie deprivation-induced RF enlargement. In contrast, visual deprivation altered short-term plasticity in an unexpected way. Specifically, GABAB receptor (GABABR)-mediated paired pulse depression was increased in slices from dark-reared animals. This increase was mimicked by GABAAR blockade in slices from normally reared animals, suggesting that experience-dependent maintenance of GABAAR function prevents an increase in probability of neurotransmitter release. GABABR-mediated short-term depression in response to strong stimulation (such as occurs during vision) was reduced in slices from dark-reared animals. This change was mimicked in slices from normal animals by reducing GABA release. These results are consistent with the hypothesis that early visual experience maintains GABAergic inhibition and prevents later deprivation-induced alterations of short-term depression in SC. Identifying how plasticity is restricted in mature circuits could guide therapies to enhance recovery of function in adults.


Asunto(s)
Potenciales Postsinápticos Excitadores/fisiología , Plasticidad Neuronal/fisiología , Receptores de GABA-B/fisiología , Colículos Superiores/crecimiento & desarrollo , Percepción Visual/fisiología , Factores de Edad , Animales , Adaptación a la Oscuridad/fisiología , Femenino , Masculino , Mesocricetus , Técnicas de Cultivo de Órganos , Colículos Superiores/citología , Campos Visuales/fisiología
19.
Artículo en Inglés | MEDLINE | ID: mdl-25071538

RESUMEN

Winner-Take-All (WTA) networks are recurrently connected populations of excitatory and inhibitory neurons that represent promising candidate microcircuits for implementing cortical computation. WTAs can perform powerful computations, ranging from signal-restoration to state-dependent processing. However, such networks require fine-tuned connectivity parameters to keep the network dynamics within stable operating regimes. In this article, we show how such stability can emerge autonomously through an interaction of biologically plausible plasticity mechanisms that operate simultaneously on all excitatory and inhibitory synapses of the network. A weight-dependent plasticity rule is derived from the triplet spike-timing dependent plasticity model, and its stabilization properties in the mean-field case are analyzed using contraction theory. Our main result provides simple constraints on the plasticity rule parameters, rather than on the weights themselves, which guarantee stable WTA behavior. The plastic network we present is able to adapt to changing input conditions, and to dynamically adjust its gain, therefore exhibiting self-stabilization mechanisms that are crucial for maintaining stable operation in large networks of interconnected subunits. We show how distributed neural assemblies can adjust their parameters for stable WTA function autonomously while respecting anatomical constraints on neural wiring.

20.
Biol Psychiatry ; 76(9): 750-8, 2014 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-24631130

RESUMEN

BACKGROUND: Current smoking cessation therapies offer limited success, as relapse rates remain high. Nicotine, which is the major component of tobacco smoke, is thought to be primarily responsible for the addictive properties of tobacco. However, little is known about the molecular mechanisms underlying nicotine relapse, hampering development of more effective therapies. The objective of this study was to elucidate the role of medial prefrontal cortex (mPFC) glutamatergic and gamma-aminobutyric acid (GABA)ergic receptors in controlling relapse to nicotine seeking. METHODS: Using an intravenous self-administration model, we studied glutamate and gamma-aminobutyric acid receptor regulation in the synaptic membrane fraction of the rat mPFC following extinction and cue-induced relapse to nicotine seeking. Subsequently, we locally intervened at the level of GABAergic signaling by using a mimetic peptide of the GABA receptor associated protein-interacting domain of GABA type A (GABAA) receptor subunit γ2 (TAT-GABAγ2) and muscimol, a GABAA receptor agonist. RESULTS: Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid and N-methyl-D-aspartate receptors were not regulated after the 30-min relapse test. However, GABAA receptor subunits α1 and γ2 were upregulated, and interference with GABAA receptor insertion in the cell membrane using the TAT-GABAγ2 peptide in the dorsal mPFC, but not the ventral mPFC, significantly increased responding during relapse. Increasing GABAA transmission with muscimol in the dorsal and ventral mPFC attenuated relapse. CONCLUSIONS: These data indicate that cue-induced relapse entails a GABAergic plasticity mechanism that limits nicotine seeking by restoring inhibitory control in the dorsal mPFC. GABAA receptor-mediated neurotransmission in the dorsal mPFC constitutes a possible future therapeutic target for maintaining smoking abstinence.


Asunto(s)
Señales (Psicología) , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Corteza Prefrontal/fisiología , Receptores de GABA-A/química , Receptores de GABA-A/metabolismo , Tabaquismo/psicología , Animales , Condicionamiento Operante/efectos de los fármacos , Extinción Psicológica/efectos de los fármacos , Agonistas de Receptores de GABA-A/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Muscimol/farmacología , Nicotina/administración & dosificación , Péptidos/administración & dosificación , Corteza Prefrontal/efectos de los fármacos , Ratas , Ratas Wistar , Receptores de Glutamato/metabolismo , Recurrencia , Autoadministración , Sinapsis/metabolismo , Ácido gamma-Aminobutírico
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