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Molecular basis of plasticity in the visual cortex
Abstract
Sensory experience is known to shape the maturation of cortical circuits during development. A paradigmatic example is the effect of monocular deprivation on ocular dominance of visual cortical neurons. Although visual cortical plasticity has been widely studied since its initial discovery by Hubel and Wiesel >40 years ago, the description of the underlying molecular mechanisms has lagged behind. Several new findings are now beginning to close this gap. Recent data deepen our knowledge of the factors involved in the intercellular communication and intracellular signaling that mediate experience-dependent plasticity in the developing visual cortex. In addition, new findings suggest a role for the extracellular matrix in inhibition of ocular-dominance plasticity in the adult visual cortex.
... A crucial issue emerging from numerous experiments is that MD plays on a mechanism of competition between the two eyes. The neurotrophic hypothesis claims that neurotrophins, synthesized and released from cortical neurons in an activity-dependent manner, are captured by the most active nerve terminals and transported retrogradely along the axons to the cell body where they exert their effect in terms of survival and strengthening of synaptic connections both at functional and morphological level (Berardi et al., 2003;Tropea et al., 2009). The transport of neurotrophic factors, however, occurs not only retrogradely, but also in anterograde direction (from the cell body to axons and dendrites) and a role for the anterograde action of BDNF in plasticity of the visual cortex has been suggested (Caleo et al., 2000). ...
... The transport of neurotrophic factors, however, occurs not only retrogradely, but also in anterograde direction (from the cell body to axons and dendrites) and a role for the anterograde action of BDNF in plasticity of the visual cortex has been suggested (Caleo et al., 2000). Other studies have shown that neurotrophins have an even more complex action in regulating plasticity processes with different effects on specific cell populations: it has been widely documented, for example, that BDNF is involved in the maturation of inhibitory neurons and NGF promotes cholinergic transmission (Berardi et al., 2003;Tropea et al., 2009). ...
... Once triggered by electrical activity, plasticity processes take place through the activation of a series of intracellular proteins, including the protein kinases PKA (protein kinase A), ERK (protein kinase regulated by extracellular signals) and CaMKII (protein calcium-calmodulin kinase dependent II), which can locally regulate the insertion of new receptors in the membrane of postsynaptic neurons or determine their removal, causing respectively a rapid increase or decrease in the synaptic response (Berardi et al., 2003;Tropea et al., 2009). ...
Brain plasticity refers to the ability of synaptic connections to adapt their function and structure in response to experience, including environmental changes, sensory deprivation and injuries. Plasticity is a distinctive, but not exclusive, property of the developing nervous system. This review introduces the concept of neuroplasticity and describes classic paradigms to illustrate cellular and molecular mechanisms underlying synapse modifiability. Then, we summarize a growing number of studies showing that the adult cerebral cortex retains a significant degree of plasticity highlighting how the identification of strategies to enhance the plastic potential of the adult brain could pave the way for the development of novel therapeutic approaches aimed at treating amblyopia and other neurodevelopmental disorders. Finally, we analyze how the visual system adjusts to neurodegenerative conditions leading to blindness and we discuss the crucial role of spared plasticity in the visual system for sight recovery.
... The molecular mechanisms underlying experience-dependent plasticity have been widely investigated in animals (Berardi et al., 2003;Heimel et al., 2011). The maturation of intracortical inhibition has been proved to play a crucial role in regulating the progression of the critical period for ocular dominance and visual acuity (Berardi et al., 2003;Fagiolini et al., 2004;Fagiolini and Hensch, 2000;Hensch et al., 1998;Huang et al., 1999;Speed et al., 1991). ...
... The molecular mechanisms underlying experience-dependent plasticity have been widely investigated in animals (Berardi et al., 2003;Heimel et al., 2011). The maturation of intracortical inhibition has been proved to play a crucial role in regulating the progression of the critical period for ocular dominance and visual acuity (Berardi et al., 2003;Fagiolini et al., 2004;Fagiolini and Hensch, 2000;Hensch et al., 1998;Huang et al., 1999;Speed et al., 1991). For instance, increasing intracortical inhibition was shown to anticipate the opening and closure of the critical period for monocular deprivation in mice (Fagiolini and Hensch, 2000;Hanover et al., 1999;Huang et al., 1999), and transgenic animals lacking a GABA-synthesizing enzyme showed deficient ocular dominance plasticity to monocular deprivation which could be restored by increasing inhibitory transmission with benzodiazepines (Hensch et al., 1998). ...
... Of course, GABAergic circuits are not the only ones mediating plasticity in visual cortex (Berardi et al., 2003). In non-human animals, ocular dominance plasticity can be restored also by enhancing excitatory neurotransmission systems such as serotoninergic (Maya Vetencourt et al., 2008) and cholinergic (Morishita et al., 2010) systems. ...
Between 1-5:100 people worldwide have never experienced normotypic vision due to a condition called amblyopia, and about 1:4000 suffer from inherited retinal dystrophies that progressively lead to blindness. While a wide range of technologies and therapies are being developed to restore vision, a fundamental question still remains unanswered: would the adult visual brain retain a sufficient plastic potential to learn how to 'see' after a prolonged period of abnormal visual experience? In this review we summarize studies showing that the visual brain of sighted adults retains a type of developmental plasticity, called homeostatic plasticity, and this property has been recently exploited successfully for adult amblyopia recovery. Next, we discuss how the brain circuits reorganize when blindness occurs and when visual stimulation is partially restored by means of a 'bionic eye' in late blind adults with Retinitis Pigmentosa. The primary visual cortex in these patients slowly became activated by the artificial visual stimulation, indicating that sight restoration therapies can rely on a considerable degree of spared plasticity in adulthood.
... The molecular mechanisms underlying experience-dependent plasticity have been widely investigated in animals (Berardi et al., 2003;Heimel et al., 2011). The maturation of intracortical inhibition has been proved to play a crucial role in regulating the progression of critical period for ocular dominance and visual acuity (Berardi et al., 2003;Fagiolini et al., 2004;Fagiolini and Hensch, 2000;Hensch et al., 1998;Huang et al., 1999;Speed et al., 1991). ...
... The molecular mechanisms underlying experience-dependent plasticity have been widely investigated in animals (Berardi et al., 2003;Heimel et al., 2011). The maturation of intracortical inhibition has been proved to play a crucial role in regulating the progression of critical period for ocular dominance and visual acuity (Berardi et al., 2003;Fagiolini et al., 2004;Fagiolini and Hensch, 2000;Hensch et al., 1998;Huang et al., 1999;Speed et al., 1991). For instance, increasing intracortical inhibition was shown to anticipate the opening and closure of the critical period for monocular deprivation in mice (Fagiolini and Hensch, 2000;Hanover et al., 1999;Huang et al., 1999), and transgenic animals lacking a GABA-synthesizing enzyme showed deficient ocular dominance plasticity to monocular deprivation which could be restored by increasing inhibitory transmission with benzodiazepines (Hensch et al., 1998). ...
... Of course GABAergic circuits are not the only ones mediating plasticity in visual cortex (Berardi et al., 2003). In animals, ocular dominance plasticity can be restored also by enhancing excitatory neurotransmission systems such as serotoninergic (Maya Vetencourt et al., 2008) and cholinergic (Morishita et al., 2010) systems. ...
Between 1 to 5 out of 100 people worldwide has never experienced normotypic vision due to a condition called amblyopia, and about 1 out of 4000 suffer from inherited retinal dystrophies that progressively lead them to blindness. While a wide range of technologies and therapies are being developed to restore vision, a fundamental question still remains unanswered: would the adult visual brain retain a sufficient plastic potential to learn how to see after a prolonged period of abnormal visual experience? In this review we summarize studies showing that the visual brain of sighted adults retains a type of developmental plasticity, called homeostatic plasticity, and this property has been recently exploited successfully for adult amblyopia recover. Next, we discuss how the brain circuits reorganizes when visual stimulation is partially restored by means of a bionic eye in late blinds with Retinitis Pigmentosa. The primary visual cortex in these patients slowly became activated by the artificial visual stimulation, indicating that sight restoration therapies can rely on a considerable degree of spared plasticity in adulthood.
... Despite the current understanding of molecular and cellular aspects of visual cortex plasticity [12,[17][18][19][20][21][22] and the well-described role of neuromodulators in brain plasticity [19,[23][24][25][26][27], only little is known about sensory deprivation-induced alterations in serotonin (5-HT) signaling across sensory areas or, in concreto, about how 5-HT is involved in the different types of cortical plasticity in the context of acquired blindness. A wide range of axonal projections, originating from the serotonergic Fig. 1 Schematic overview of the different cortical plasticity phases occurring in the adult ME-mouse model and illustration of the experimental setup. ...
... In the visual cortex, five subregions can be distinguished from lateral to medial (Figs. 1c, 5): the lateral extrastriate cortex (V2L), which is subdivided into a monocular (V2Lm, segments 1-4) and binocular region (V2Lb, segments 4-8), the primary visual cortex (V1) which is subdivided further into a binocular (V1b, segments 8-15) and monocular region (V1 m, segments [15][16][17][18][19][20][21], and the medial extrastriate cortex (V2M, segments [21][22][23][24] [51,53,56,89]. For the zif268 analysis, we focused specifically on the Bz (V2Lb-V1b) and the Mmz (V1 m-V2M) as these regions undergo open-eye potentiation and cross-modal plasticity respectively. ...
... In the visual cortex, five subregions can be distinguished from lateral to medial (Figs. 1c, 5): the lateral extrastriate cortex (V2L), which is subdivided into a monocular (V2Lm, segments 1-4) and binocular region (V2Lb, segments 4-8), the primary visual cortex (V1) which is subdivided further into a binocular (V1b, segments 8-15) and monocular region (V1 m, segments [15][16][17][18][19][20][21], and the medial extrastriate cortex (V2M, segments [21][22][23][24] [51,53,56,89]. For the zif268 analysis, we focused specifically on the Bz (V2Lb-V1b) and the Mmz (V1 m-V2M) as these regions undergo open-eye potentiation and cross-modal plasticity respectively. ...
Visual cortical areas show enhanced tactile responses in blind individuals, resulting in improved behavioral performance. Induction of unilateral vision loss in adult mice, by monocular enucleation (ME), is a validated model for such cross-modal brain plasticity. A delayed whisker-driven take-over of the medial monocular zone of the visual cortex is preceded by so-called unimodal plasticity, involving the potentiation of the spared-eye inputs in the binocular cortical territory. Full reactivation of the sensory-deprived contralateral visual cortex is accomplished by 7 weeks post-injury. Serotonin (5-HT) is known to modulate sensory information processing and integration, but its impact on cortical reorganization after sensory loss, remains largely unexplored. To address this issue, we assessed the involvement of 5-HT in ME-induced cross-modal plasticity and the 5-HT receptor (5-HTR) subtype used. We first focused on establishing the impact of ME on the total 5-HT concentration measured in the visual cortex and in the somatosensory barrel field. Next, the changes in expression as a function of post-ME recovery time of the monoamine transporter 2 (vMAT2), which loads 5-HT into presynaptic vesicles, and of the 5-HTR1A and 5-HTR3A were assessed, in order to link these temporal expression profiles to the different types of cortical plasticity induced by ME. In order to accurately pinpoint which 5-HTR exactly mediates ME-induced cross-modal plasticity, we pharmacologically antagonized the 5-HTR1A, 5-HTR2A and 5-HTR3A subtypes. This study reveals brain region-specific alterations in total 5-HT concentration, time-dependent modulations in vMAT2, 5-HTR1A and 5-HTR3A protein expression and 5-HTR antagonist-specific effects on the post-ME plasticity phenomena. Together, our results confirm a role for 5-HTR1A in the early phase of binocular visual cortex plasticity and suggest an involvement of 5-HTR2A and 5-HTR3A but not 5-HTR1A during the late cross-modal recruitment of the medial monocular visual cortex. These insights contribute to the general understanding of 5-HT function in cortical plasticity and may encourage the search for improved rehabilitation strategies to compensate for sensory loss.
... Alteration in the pattern of function and expression of ion channels, such as calcium and sodium channels (Navs 1.1, 1.2 and Navs 1.6-1.9), are potential contributors to genesis and maintenance of neuropathic pain after injury because they promote electrophysiological modifications, not only at the axotomized site but in neighboring uninjured fibers [8,27,36,37,[41][42][43][44][45]. Furthermore, they have their altered expression and function generating ectopic firing, contributing to sensations of hyperalgesia and allodynia, the latter being related to the interaction of up-regulation of the α2δ subunit of the calcium channel, with neurokinin-1 receptors, p38 MAPK, P2X4 and neuronal c-jun deletion, also contributing to neuropathic pain and hyperalgesia. ...
... Structural rearrangement is also associated with the development of aberrant neuronal circuits, among other changes and dysfunctions arising from structural rearrangement, and other genes, such as β2-microglobulin (TAP1), and molecules, such as MHC I, may contribute to nociceptive reactions and impaired peripheral neuroregeneration. In addition, structural rearrangement alters the expression of AMPA, NMDA and GABAergic receptors also have a role in the mechanism of neuropathic pain, where there is a decrease in GABAergic receptors and an increase in AMPA and NMDA expression at the synaptic membrane through activation of several pathways, such as PKC, PKA and CMAK2 cascades [3,8,16,27,[36][37][38][39][40][41][42][43][44][45]. ...
Neuroplasticity differs from neuroregeneration, although both phenomena propose functional recovery after injury. The difference between both is evidenced in terms of recovery time, molecular reaction, gene and molecular expression, as well as conceptual. In this paper, we show the process of peripheral neuroregeneration and some differences between the neuroplasticity of the peripheral and central nervous system, as well as some complications of the process of neuroregeneration of the peripheral nervous system. To carry out the work, the PubMed platform was used with two batteries of descriptors to find the articles, in addition to filters that the platform provides for the selection of articles. In addition, some authors found in the platform search suggested the reading of other articles and these were included in this work according to the inclusion and exclusion methods. The process of peripheral neuroregeneration is complex, involving many signaling pathways, inflammatory and cellular response, and gene expression that favor neuroregeneration. It can be concluded that the mechanism of neuroregeneration consists of three main pillars that are pro-regenerative gene expression, inflammatory response, and Schwann cell action. However, it is not a perfect mechanism, and some complications have been evidenced.
... The NMDAR subtypes mediating neurotransmission in V1 change over the developmental period, similar to those seen in hippocampus or somatosensory cortex (Liu et al. 2004), where the slower, NR2B subunits are less evident in the adult and are replaced by NMDAR with faster, NR2A subunits (Nase et al. 1999). NMDAR with NR2B have been shown to play an important role in plastic changes in rodent V1 circuits during development (Berardi et al. 2003;Li and Wang 2013), in addition to classic cAMP-PKA signaling events that can strengthen connections (Berardi et al. 2003). Although the ratio of NMDAR/AMPAR ratio appears similar between V1 and medial PFC in the rodent (Myme et al. 2003), there is less NR2B expression in V1 compared with the medial PFC (Wang et al. 2008), where NMDAR currents have been related to the recurrent firing needed for working memory (Wang et al. 2008). ...
... The NMDAR subtypes mediating neurotransmission in V1 change over the developmental period, similar to those seen in hippocampus or somatosensory cortex (Liu et al. 2004), where the slower, NR2B subunits are less evident in the adult and are replaced by NMDAR with faster, NR2A subunits (Nase et al. 1999). NMDAR with NR2B have been shown to play an important role in plastic changes in rodent V1 circuits during development (Berardi et al. 2003;Li and Wang 2013), in addition to classic cAMP-PKA signaling events that can strengthen connections (Berardi et al. 2003). Although the ratio of NMDAR/AMPAR ratio appears similar between V1 and medial PFC in the rodent (Myme et al. 2003), there is less NR2B expression in V1 compared with the medial PFC (Wang et al. 2008), where NMDAR currents have been related to the recurrent firing needed for working memory (Wang et al. 2008). ...
Neurons in primary visual cortex (V1) are more resilient than those in dorsolateral prefrontal cortex (dlPFC) in aging, schizophrenia and Alzheimer's disease. The current study compared glutamate and neuromodulatory actions in macaque V1 to those in dlPFC, and found striking regional differences. V1 neuronal firing to visual stimuli depended on AMPA receptors, with subtle NMDA receptor contributions, while dlPFC depends primarily on NMDA receptors. Neuromodulatory actions also differed between regions. In V1, cAMP signaling increased neuronal firing, and the phosphodiesterase PDE4A was positioned to regulate cAMP effects on glutamate release from axons. HCN channels in V1 were classically located on distal dendrites, and enhanced cell firing. These data contrast with dlPFC, where PDE4A and HCN channels are concentrated in thin spines, and cAMP-HCN signaling gates inputs and weakens firing. These regional differences may explain why V1 neurons are more resilient than dlPFC neurons to the challenges of age and disease.
... The hypothesis that different levels of maternal care in enriched condition could induce the precocious development of the visual system in enriched animals is also suggested by results showing that variations in maternal care can affect BDNF levels and neural development of the offspring (Liu et al., 1997). Neurotrophins, and in particular, BDNF, have a major role in the control of visual cortical plasticity during a critical period early in life (reviewed in Berardi et al., 2003). ...
... Neurotrophins have a major role in the control of visual cortical plasticity during a critical period early in life (reviewed in Berardi et al., 2003). In particular, BDNF exerts profound influence on the development of the visual system. ...
This chapter describes experimental evidence clearly indicating that the development of the mammalian brain results from the combination of multiple internal and external inputs, ultimately modifying expression levels of neurotrophins (NTs), shaping the nervous system. NTs, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), play a pivotal role in brain development and plasticity representing good candidates for mediating some of the effects triggered by early experiences on brain function. BDNF and serotonin are two seemingly distinct signaling systems that play regulatory roles in many neuronal functions including survival, neurogenesis, and synaptic plasticity. The continuous refinement of brain circuits through activity-dependent mechanisms allows for external manipulations to sculpt and refine connections in the brain, offering potential for therapeutic intervention when a derangement in plasticity might occur. Epigenetics is perfectly suited to provide a mechanism underlying the effects of gene by environment interactions.
... From their extensive research on vision and plasticity, Hubel and Wiesel (1963) reported that neurons in the primary visual cortex of the kitten became unresponsive after elimination of visual input to the eye because of poor synapse formation from the lateral geniculate body to the visual cortex (Hubel and Wiesel 1963). Since then, increased attention has been given to visual cortex reorganization, particularly in peripheral vision disorders (Berardi et al. 2003;Maya-Vetencourt and Pizzorusso 2013;Papanikolaou et al. 2014). Regarding stroke, there are a few reports about visual functional reorganization in infants but with an unexpected absence of visual field deficits (Bova et al. 2008;Guzzetta et al. 2013). ...
Brain mapping during awake craniotomy for gliomas can help preserve neurological functions, including maintenance of central and peripheral vision. However, the consecutive changes in the visual field remain unknown. We retrospectively assessed 14 patients who underwent awake craniotomy for gliomas infiltrating into the optic radiation. Cortico-subcortical direct electrical stimulation (DES) was intraoperatively applied until transient visual symptoms were elicited and recorded. The visual fields were examined consecutively in the preoperative period and postoperative subacute and chronic periods. To evaluate the anatomo-functional validity of the recordings, all DES-elicited points were overlaid onto a three-dimensional template that included the optic radiation, using voxel-based morphometry (VBM) mapping. All patients experienced visual symptoms that were classified as phosphenes, blurred vision, or hallucinations during DES, and surgical resection was limited to within the functional boundaries. In VBM, almost all the subcortical positive mapping points overlapped with the surface of the optic radiation, and the distribution of sites that induced visual phenomena in the upper or lower visual fields could be differentiated in the anatomical space. We observed no postoperative visual deficit in four patients (29%), time-dependent improvements in five out of eight patients that presented transient quadrantanopia or partial visual defect (36% out of 57%), and permanent hemianopsia (14%) in two patients with occipital lesions. Intraoperative DES that identifies and preserves optic radiation in awake craniotomy for gliomas is a reliable and effective technique to reduce risk of permanent deficits, but has a low success rate in patients with occipital involvement.
... The main visual deficits in amblyopia include impairments of VA and of CS (Levi et al., 2002;. Until recent times, amblyopia was thought to be untreatable outside the first decade of life due to reduced plasticity of the visual cortex (Berardi et al., 2003;Epelbaum et al., 1993;Loudon et al., 2002). However, several studies demonstrated that the visual system maintains a certain level of plasticity in adulthood, too (Poggio et al., 1992;Sagi, 2011;Schoups et al., 1995). ...
Background:
Vision is the sense which we rely on the most to interact with the environment and its integrity is fundamental for the quality of our life. However, around the globe, more than 1 billion people are affected by debilitating vision deficits. Therefore, finding a way to treat (or mitigate) them successfully is necessary.
Objective:
This narrative review aims to examine options for innovative treatment of visual disorders (retinitis pigmentosa, macular degeneration, optic neuropathy, refractory disorders, hemianopia, amblyopia), especially with Perceptual Learning (PL) and Electrical Stimulation (ES).
Methods:
ES and PL can enhance visual abilities in clinical populations, inducing plastic changes. We describe the experimental set-up and discuss the results of studies using ES or PL or their combination in order to suggest, based on literature, which treatment is the best option for each clinical condition.
Results:
Positive results were obtained using ES and PL to enhance visual functions, for example, repetitive transorbital Alternating Current Stimulation (rtACS) appeared as the most effective treatment for pre-chiasmatic disorders such as optic neuropathy. A combination of transcranial Direct Current Stimulation (tDCS) and visual training seems helpful for people with hemianopia, while transcranial Random Noise Stimulation (tRNS) makes visual training more efficient in people with amblyopia and mild myopia.
Conclusions:
This narrative review highlights the effect of different ES montages and PL in the treatment of visual disorders. Furthermore, new options for treatment are suggested. It is noteworthy to mention that, in some cases, unclear results emerged and others need to be more deeply investigated.
... Perineuronal nets envelop cPVins and their synapses as developmental windows of plasticity close (Pizzorusso et al., 2002;Berardi et al., 2003;McGee et al., 2005;Nowicka et al., 2009;Carulli et al., 2010;Beurdeley et al., 2012;Ye and Miao, 2013;Happel et al., 2014;Krishnan et al., 2015;Balmer, 2016). This deposition occurs in an activity dependent manner (Reimers et al., 2007;Favuzzi et al., 2017); in fact, cPVin activity is necessary for PNN assembly (Cisneros-Franco and de Villers-Sidani, 2019). ...
Parvalbumin-positive neurons are the largest class of GABAergic, inhibitory neurons in the central nervous system. In the cortex, these fast-spiking cells provide feedforward and feedback synaptic inhibition onto a diverse set of cell types, including pyramidal cells, other inhibitory interneurons, and themselves. Cortical inhibitory networks broadly, and cortical parvalbumin-expressing interneurons (cPVins) specifically, are crucial for regulating sensory plasticity during both development and adulthood. Here we review the functional properties of cPVins that enable plasticity in the cortex of adult mammals and the influence of cPVins on sensory activity at four spatiotemporal scales. First, cPVins regulate developmental critical periods and adult plasticity through molecular and structural interactions with the extracellular matrix. Second, they activate in precise sequence following feedforward excitation to enforce strict temporal limits in response to the presentation of sensory stimuli. Third, they implement gain control to normalize sensory inputs and compress the dynamic range of output. Fourth, they synchronize broad network activity patterns in response to behavioral events and state changes. Much of the evidence for the contribution of cPVins to plasticity comes from classic models that rely on sensory deprivation methods to probe experience-dependent changes in the brain. We support investigating naturally occurring, adaptive cortical plasticity to study cPVin circuits in an ethologically relevant framework, and discuss recent insights from our work on maternal experience-induced auditory cortical plasticity.
... This review focuses on how sensory deprivation impacts these multiple aspects of extracellular and cellular structure within the brain with a particular emphasis on the S1BF, similar findings have been observed in other sensory systems (Berardi et al., 2003;Persic et al., 2020;Baroncelli and Lunghi, 2021) but are beyond the focus of the current review. In characterizing structural plasticity, researchers traditionally focused on fixed tissue preparations. ...
Cellular structures provide the physical foundation for the functionality of the nervous system, and their developmental trajectory can be influenced by the characteristics of the external environment that an organism interacts with. Historical and recent works have determined that sensory experiences, particularly during developmental critical periods, are crucial for information processing in the brain, which in turn profoundly influence neuronal and non-neuronal cortical structures that subsequently impact the animals’ behavioral and cognitive outputs. In this review, we focus on how altering sensory experience influences normal/healthy development of the central nervous system, particularly focusing on the cerebral cortex using the rodent whisker-to-barrel system as an illustrative model. A better understanding of structural plasticity, encompassing multiple aspects such as neuronal, glial, and extra-cellular domains, provides a more integrative view allowing for a deeper appreciation of how all aspects of the brain work together as a whole.
... However, recent research has shown the possibility of brain plasticity in adults. Several studies have found that after monocular deprivation (a model of amblyopia), binocular activity was recovered with appropriate stimulation in adulthood (Berardi et al. 2003;Fagiolini and Hensch 2000;He et al. 2006He et al. , 2007Spolidoro et al. 2009). Furthermore, anatomical and functional neural changes have been described (Bonaccorsi et al. 2014;Antonini et al. 1999;Mataga et al. 2004;Oray et al. 2004). ...
Amblyopia or lazy eye is a dysfunction of the visual system that appears during childhood and traditionally has been considered untreatable in adults. Its main consequences are the loss of visual acuity and contrast sensitivity of the amblyopic eye and binocular vision impairments. During the last years videogames have been used as a therapeutic tool for amblyopia with the inconclusive results. The present work has assessed the effectiveness of a virtual reality videogame (AmbliOK®) in the neurorehabilitation of four adult clinical cases with anisometropic amblyopia. Visual acuity, contrast sensitivity, stereopsis and interocular suppression were assessed before, during, immediately after, one month and one year (in one patient) after the training. The intervention was conducted along four weeks (10 h) and yielded the variable results. In general, all patients showed an improvement in visual functions although not all ameliorated in the same way. Visual acuity measures improved in all patients, falling outside the amblyopia criterion at the end of the treatment. However, the improvement was not maintained one month later in two patients. Contrast sensitivity progressively improved for the amblyopic and the fellow eyes with all patients showing better results one month after the treatment. The patient assessed one year after still showed better results than in the baseline. Patients showing bad stereopsis in the baseline reached a performance considered normal one month and even one year after the treatment. The effectiveness of the treatment seems to be related to the characteristics of patients.
... It is known that the maturation of GABA-mediated intracortical inhibitory connections plays a pivotal role in the onset and closure of the critical period for the visual system [93,94]. Indeed, a study on animals with monocular deprivation but also lacking a GABAsynthesizing enzyme resulted in no ocular domination of the non-occluded eye [95]. ...
Brain plasticity is the capacity of cerebral neurons to change, structurally and functionally, in response to experiences. This is an essential property underlying the maturation of sensory functions, learning and memory processes, and brain repair in response to the occurrence of diseases and trauma. In this field, the visual system emerges as a paradigmatic research model, both for basic research studies and for translational investigations. The auditory system remains capable of reorganizing itself in response to different auditory stimulations or sensory organ modification. Acoustic biofeedback training can be an effective way to train patients with the central scotoma, who have poor fixation stability and poor visual acuity, in order to bring fixation on an eccentrical and healthy area of the retina: a pseudofovea. This review article is focused on the cellular and molecular mechanisms underlying retinal sensitivity changes and visual and auditory system plasticity.
... BDNF/TrkB is known to regulate VCx activity from development to adult life by modulating GABA inhibition and cortical plasticity [61]. Alterations of BDNF and TrkB expression in VCx in animal models of retina lesion and ocular occlusion result in a decrease of GABA release and GAD65 expression, which are associated with visual impairment and/or a delay of recovery [62][63][64]. ...
Eye-drop recombinant human nerve growth factor (ed-rhNGF) has proved to recover the retina and optic nerve damage in animal models, including the unilateral optic nerve crush (ONC), and to improve visual acuity in humans. These data, associated with evidence that ed-rhNGF stimulates the brain derived neurotrophic factor (BDNF) in retina and cortex, suggests that NGF might exert retino-fugal effects by affecting BDNF and its receptor TrkB. To address these questions, their expression and relationship with the GABAergic and glutamatergic transmission markers, GAD65 and GAD67, vesicular inhibitory amino acid transporter (VGAT), and vesicular glutamate transporters 1 and 2 (VGLUT-1 and VGLUT-2) were investigated in adult ONC rats contralateral and ipsilateral visual cortex (VCx). Ed-rhNGF recovers the ONC-induced alteration of GABAergic and glutamatergic markers in contralateral VCx, induces an upregulation of TrkB, which is positively correlated with BDNF precursor (proBDNF) decrease in both VCx sides, and strongly enhances TrkB+ cell soma and neuronal endings surrounded by GAD65 immuno-reactive afferents. These findings contribute to enlarging the knowledge on the mechanism of actions and cellular targets of exogenously administrated NGF, and suggest that ed-rhNGF might act by potentiating the activity-dependent TrkB expression in GAD+ cells in VCx following retina damage and/or ONC.
... And the grey matter volume made up of neural cells, was significant decreased in myopic subjects [10] . Moreover, concentrations of gamma-aminobutyric acid (which are vital to initiate the critical period plasticity during visual development [11] ) and its receptors in visual cortex were increased in myopic animals [12] . These evidences suggested that visual cortex might also play an important role in myopia. ...
AIM: To explore whether low myopia would affect cerebral visual functions by comparing perceptual eye position (PEP), fixation stability and stereoacuity tests between low myopic and normal adolescents. METHODS: Totally 120 adolescents matched in age and gender participated in our study. Subjects were divided into three groups according to their refractive states. The cerebral visual functions tested in our study included perceptual eye position (PEP), fixation stability and stereoacuity. Stereoacuity tests involved in our study could be categorized into two parts. The first part was classical stereo tests including Titmus and synoptophore stereo test. The second part was 3D random-dot test for zero-order stereoacuity (hereinafter as zero-order test) at different viewing distances (0.8 m and 1.5 m). RESULTS: The deviation of horizontal PEP was significantly larger in non-anisometropia when compared to control group. Both horizontal and vertical PEP bias pixels were significantly larger in anisometropia group. Both non-anisometropia group and anisometropia group had more trouble in holding their fixation stable. Moreover, anisometropia group had more abnormal results than other two groups. And in zero-order test at 1.5 m, both non-anisometropia and anisometropia had more abnormal results in stereoacuity than control group. The correlation between fixation stability and near stereoacuity (Titmus and zero-order stereoacuity at 0.8 m) was weak and positive. CONCLUSION: Low myopic adolescents still have certain defects in cerebral visual functions. Examinations used in our study are useful in assessing cerebral visual functions. They could provide better follow-up evaluation and solid ground for further specific treatments in treating defects of cerebral visual functions. So far, local retinal environment has been the focus of the development in myopia. Our results suggested that researchers might pay more attention on visual cortex in studying the mechanisms of myopia in the near future.
... They surround groups of neurons and synapses on cell bodies primarily in the mature brain, comprising a specialized form of the extracellular matrix; constituents include hyaluronan, lecticans, and several other kinds of CSPGs (61,62). Perineuronal nets attracted particular interest as brain structures that appear to be implicated in terminating the critical period for neuronal plasticity (63). Here a crucial function for tenascin-R began to emerge; it appears to be essential for the normal development of perineuronal nets. ...
... For example, cortical infusion of a GAD inhibitor promotes plasticity in adult V1 (Berardi et al., 2003). Adult rats exposed to complete darkness, show reduced expression of GABA A receptors, thus altering the excitation/inhibition balance and enhancing V1 plasticity (He et al., 2007). ...
During postnatal development, the cerebral cortex has limited temporal periods of high plasticity, called critical periods (CPs). These windows, which allow neural circuitry to be shaped by external stimuli, are found in many cortical regions and are regulated by several factors that influence the balance between excitation and inhibition. The most studied CP is that of ocular dominance in the visual cortex, and the OTX2 homeoprotein transcription factor plays an essential role. OTX2 is transferred from extra-cortical sources into a specific class of interneurons, the parvalbumin (PV) cells, and this transfer controls CP onset and closure in several cortical regions. The aim of my thesis was to reveal the mechanisms underlying OTX2 non-cell autonomous activity implicated in CP regulation. Altogether my work extends our current understanding of cortical plasticity and the role of OTX2 during CPs. I have shown that non-cell autonomous OTX2 regulates cortical postnatal plasticity through direct transcriptional mechanisms and epigenetic modifications.
... The extracellular matrix forms such typical morphological assemblies around select neuronal compartments called perineuronal nets [14,38] or axonal coats [18,48] around the somatodendritic part and the terminal axon segment, respectively. First misidentified for staining artefacts [20], perineuronal nets were explored to surround specific subsets of neurons, possibly to protect against stress and neurodegeneration [17,53,54], to maintain a select pericellular micromillieu [14] or to govern synaptic remodeling [10,44,61]. Dehiscences in this lattice-like structure mark synaptic sites which were formed prior to matrix accumulation around the cell body [59]. ...
Composition of the brain extracellular matrix changes in time as maturation proceeds. Chondroitin sulfate proteoglycan 5 (CSPG-5), also known as neuroglycan C, has been previously associated to differentiation since it shapes neurite growth and synapse forming. Here, we show that this proteoglycan persists in the postnatal rat brain, and its expression is higher in cortical regions with plastic properties, including hippocampus and the medial prefrontal cortex at the end of the second postnatal week. Progressively accumulating after birth, CSPG-5 typically concentrates around glutamatergic and GABAergic terminals in twelve-week old rat hippocampus. CSPG-5-containing perisynaptic matrix rings often appear at the peripheral margin of perineuronal nets. Electron microscopy and analysis of synaptosomal fraction showed that CSPG-5 accumulates around, and is associated to synapses, respectively. In vitro analyses suggest that neurons, but less so astrocytes, express CSPG-5 in rat primary neocortical cultures, and CSPG-5 produced by transfected neuroblastoma cells appear at endings and contact points of neurites. In human subjects, CSPG-5 expression shifts in brain areas of the default mode network of suicide victims, which may reflect an impact in the pathogenesis of psychiatric diseases or support diagnostic power.
... Until relatively recently, work done in a variety of animal models suggested that both the structural (also see Figure 2b). Excitatory activity also triggers the production of brain-derived neurotrophic factor (BDNF, mice, [31]; Figure 2d) which, in conjunction with neural activity, actively promotes the maturation of inhibitory [34]. GABAergic processes are regulated by molecular signaling, each governing different types of inhibitory interneurons (e.g., NRG1/Erb4 for PV neurons [35] and IGF1 gene for vasoactive intestinal peptide-expressing neurons [36] in mice). ...
The human brain contains 100 billion neurons, and each neuron can have up to 200,000 connections to other neurons. Recent advancements in neuroscience—ranging from molecular studies in animal models to behavioral studies in humans—have given us deeper insights into the development of this extraordinarily intricate system. Studies show a complex interaction between biological predispositions and environment; while the gross neuroanatomy and low-level functions develop early prior to receiving environmental inputs, functional selectivity is shaped through experience, governed by the maturation of local excitatory and inhibitory circuits and synaptic plasticity during sensitive periods early in development. Plasticity does not end with the closing of the early sensitive period – the environment continues to play an important role in learning throughout the lifespan. Recent work delineating the cascade of events that initiates, controls and ends sensitive periods, offers new hope of eventually being able to remediate various clinical conditions by selectively reopening plasticity.
... However, newborn's visual functions are very different from adult's visual functions, because of differences in visual receptive fields (RFs), that constitute regions in the visual field where a visual cell responds to visual stimuli [7,8]. In fact, maturation of the visual system and particularly of V1 is very long and strongly influenced by visual experience during the early stages of life, thanks to brain plasticity [3,9], that refers to the brain's ability to undergo functional and structural alterations in response to internal and external environmental changes [10]. ...
Background
Vision is an adaptive function and should be considered a prerequisite for neurodevelopment because it permits the organization and the comprehension of the sensory data collected by the visual system during daily life. For this reason, the influence of visual functions on neuromotor, cognitive, and emotional development has been investigated by several studies that have highlighted how visual functions can drive the organization and maturation of human behavior. Recent studies on animals and human models have indicated that visual functions mature gradually during post-natal life, and its development is closely linked to environment and experience.
Discussion
The role of vision in early brain development and some of the neuroplasticity mechanisms that have been described in the presence of cerebral damage during childhood are analyzed in this review, according to a neurorehabilitation prospective.
... However, the focus on the physiological role of BDNF has shifted recently to a critical mediator of activity-dependent neuronal plasticity in the developing and adult central nervous system via balancing between anabolic (BDNF-TrkB signaling) and catabolic (BDNF-p75 signaling) effects on plasticity (Deppmann et al., 2008;Lu et al., 2014). According to this complex scenario for BDNF-driven neuronal plasticity, BDNF has apparently opposite effects on the plasticity in the visual cortex during the critical developing period and in adulthood, which has been extensively studied and characterized by the monocular deprivation technique in animal models (Berardi et al., 2003;Hensch, 2005;Vetencourt et al., 2008;Wiesel and Hubel, 1965). As for affective brain network, adolescence is a critical period in development characterized by significant changes in affective regulation and its underlying hormonal and neural correlates including the hypothalamic-pituitary-adrenal axis, amygdala, and prefrontal cortex (Tottenham and Galvan, 2016). ...
... In our previous study, we applied iTBS coinciding with the acute period after stroke (Barry et al., 2014), when axonal sprouting is high and when iTBS had the potential to facilitate new synapse formation and consequently enhance recovery. In contrast, the present study applied iTBS during the sub-acute and later chronic phases of recovery, coinciding with periods where axonal sprouting was decreasing and alongside the steady up-regulation of peri-neuronal nets working to prevent new synapse formation (Berardi et al., 2003;Rhodes and Fawcett, 2004;Carmichael et al., 2005). At the later delayed time point, the low dose of stimulation may have been insufficient to perturb these processes. ...
Targeting interhemispheric inhibition using brain stimulation has shown potential for enhancing stroke recovery. Following stroke, increased inhibition originating from the contralesional hemisphere impairs motor activation in ipsilesional areas. We have previously reported that low-intensity electrical theta burst stimulation (TBS) applied to an implanted electrode in the contralesional rat motor cortex reduces interhemispheric inhibition, and improves functional recovery when commenced three days after cortical injury. Here we apply this approach at more clinically relevant later time points and measure recovery from photothrombotic stroke, following three weeks of low-intensity intermittent TBS (iTBS), continuous TBS (cTBS) or sham stimulation applied to the contralesional motor cortex. Interhemispheric inhibition and cellular excitability were measured in the same rats from single pyramidal neurons in the peri-infarct area, using in vivo intracellular recording. A minimal dose of iTBS did not enhance motor function when applied beginning one month after stroke. However both a high and a low dose of iTBS improved recovery to a similar degree when applied 10 days after stroke, with the degree of recovery positively correlated with ipsilesional excitability. The final level of interhemispheric inhibition was negatively correlated with excitability, but did not independently correlate with functional recovery. In contrast, contralesional cTBS left recovery unaltered, but decreased ipsilesional excitability. These data support focal contralesional iTBS and not cTBS as an intervention for enhancing stroke recovery and suggest that there is a complex relationship between functional recovery and interhemispheric inhibition, with both independently associated with ipsilesional excitability.
... This evidence is in line with REM sleep-dependent dendritic spine alterations and molecular mechanisms of adult learning and development in the motor cortex [114]. In conclusion, despite the many differences that exist between developing and adult animals, they share key activitydependent mechanisms of memory consolidation during NREM and REM sleep [114,248,249]. ...
Once viewed as a passive physiological state, sleep is a heterogeneous and complex sequence of brain states with essential effects on synaptic plasticity and neuronal functioning. Rapid-eye-movement (REM) sleep has been shown to promote calcium-dependent plasticity in principal neurons of the cerebral cortex, both during memory consolidation in adults and during post-natal development. This article reviews the plasticity mechanisms triggered by REM sleep, with a focus on the emerging role of kinases and immediate-early genes for the progressive corticalization of hippocampus-dependent memories. The body of evidence suggests that memory corticalization triggered by REM sleep is a systemic phenomenon with cellular and molecular causes.
... Glutamate-gated AMPA and NMDA receptors regulate intracellular calcium level. As a second messenger, calcium activates many intracellular signaling cascades mainly including three critical kinases (ERK: called ERK, extracellular signal-regulated kinases; PKA: protein kinase A; and CaMKII alpha: calcium/calmodulin-dependent protein kinase II alpha) [101][102][103][104]. These kinases may modulate synaptic strength and induce plasticity by phosphorylating plasticityregulating molecules or mediating changes in target gene transcription synaptic signaling molecules by activating C-AMP response element-binding protein (CREB) [105]. ...
... This plasticity declines with age. 26 For the segregation to be successful, it is crucial to maintain a balance between excitation and inhibition. 11 Even small alterations to inhibitory neurotransmission can result in profound effects on visual cortex plasticity. ...
The network hypothesis of depression proposes that mood disorders reflect problems in information processing within particular neural networks. Antidepressants, including selective serotonin reuptake inhibitors (SSRIs), function by gradually improving information processing within these networks. Antidepressants have been shown to induce a state of juvenile‐like plasticity comparable to that observed during developmental critical periods: such critical‐period‐like plasticity allows brain networks to better adapt to extrinsic and intrinsic signals. We have coined this drug‐induced state of juvenile‐like plasticity iPlasticity. A combination of iPlasticity induced by chronic SSRI treatment together with training, rehabilitation, or psychotherapy improves symptoms of neuropsychiatric disorders and issues underlying the developmentally‐ or genetically‐malfunctioning networks. We have proposed that iPlasticity might be a critical component of antidepressant action. We have demonstrated that iPlasticity occurs in the visual cortex, fear erasure network, extinction of aggression caused by social isolation, and spatial reversal memory in rodent models. Chronic SSRI treatment is known to promote neurogenesis and to cause dematuration of granule cells in the dentate gyrus and of interneurons, especially parvalbumin interneurons enwrapped by perineuronal nets in the prefrontal cortex, visual cortex, and amygdala. Brain‐derived neurotrophic factor (BDNF), via its receptor Tropomyosin kinase receptor B (TrkB), is involved in processes of the synaptic plasticity, including neurogenesis, neuronal differentiation, weight of synapses, and gene regulation of synaptic formation. BDNF can be activated by both chronic SSRI treatment and neuronal activity. Accordingly, the BDNF/TrkB pathway is critical for iPlasticity, but further analyses will be needed to provide mechanical insight into the processes of iPlasticity.
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... Amblyopia was thought to be treatable only if diagnosed within the critical period, that is before ten years of age (Epelbaum et al., 1993;Greenwald and Parks, 1999), due to aged-diminished neural plasticity within the visual cortex that would limit any anatomical, physiological or functional changes (Berardi et al., 2003). Nonetheless, recent studies have reported improvements beyond this period in healthy adults, related to various visual functions following perceptual training (Fiorentini and Berardi, 1981;Karni and Sagi, 1991;Poggio et al., 1992;Sagi, 2011;Schoups et al., 1995); suggesting neuronal plasticity at early levels of the adult visual system (Pourtois et al., 2008;Schoups et al., 2001). ...
Amblyopia is a neuro-developmental disorder characterised by several functional impairments in spatial vision even with the best optical correction. There is evidence that extensive perceptual training can improve visual acuity (VA) and contrast sensitivity (CS) in adults with amblyopia. In the present study, we assessed the efficacy of a recently developed neuro-modulatory technique (i.e., high-frequency transcranial random noise stimulation; hf-tRNS) combined with a short perceptual training in adults with amblyopia. One group of ten participants underwent a short (8 sessions) monocular training in a contrast detection task with concurrent hf-tRNS, whereas another group of ten participants underwent the same training protocol but with Sham stimulation (control group). The training consisted of a two-interval forced choice (2IFC) contrast detection task in which participants had to detect the presence of a central Gabor patch flanked by two high-contrast collinear Gabors (lateral masking). The results showed a significant and similar improvement of CS for both groups, suggesting that hf-tRNS is not crucial for the improvement of CS. However, for VA, a significant improvement was only observed in the hf-tRNS group with a mean VA improvement of 0.19 LogMAR in the amblyopic eye. Most notably, this improvement was achieved after eight training sessions. The results are discussed in terms of the influence of hf-tRNS on short-term neural plasticity.
... First, plasticity can be reopened in the adults by resetting the immature lower level of inhibition: exposure of adult animals to darkness (He et al., 2007) as well as administration of an antagonist of GABA A R (Berardi et al., 2003) enhance ODP. Accordingly, transplanting embryonic inhibitory neurons in the postnatal visual cortex was shown to restore plasticity (Southwell et al., 2010;Tang et al., 2014;Davis et al., 2015). ...
The maturation of sensory processing undergoes a critical period (CP), during which cortical neural circuits are sculpted and changed by experience. The closure of CP is paralleled by the accumulation of extracellular perineuronal nets (PNN) around parvalbumin (PV)-positive interneurons. The degradation of PNNs in adult animals was shown to re-open the structural plasticity typical of the CP. We aimed at defining i) the neurophysiological properties of PV cells and principal neurons in layer 4 of primary visual cortex (V1) during the establishment of the CP ii) how these properties are altered by PNN accumulation. We found a robust age-dependent increase of input-output firing relationships in both cell types. Importantly, in vivo PNN removal in adult V1 increased both excitatory and inhibitory transmission selectively onto PV, leaving their excitability intact, and recapitulating younger states. In addition, triggering plasticity in vivo by monocular deprivation did not boost the increased activity onto PV cells. Interestingly, paired recordings in layer 4 showed no changes of inhibitory unitary connections, with or without PNNs. In order to understand the circuit mechanisms underlined, we expressed the light-sensitive opsin ChR2 in the visual thalamus. We found that PNN removal increases the recruitment of PV cells by thalamocortical fibers leading to an increase of feedforward inhibition. These results are in agreement with V1 recordings in vivo of visually evoked potentials in response of increasing contrast. Indeed, PNN disruption caused a reduction of the slope of the contrast sensitivity curve, indicating a higher recruitment of inhibition.
... This initial and transient reduction of PV cell activity establishes the conditions necessary for the experiencedependent excitatory cortical plasticity for ocular dominance. Previous studies identified neurotrophins, extracellular matrix components, and synapse formation molecules as modulators of visual cortical plasticity (Berardi, Pizzorusso, Ratto, & Maffei, 2003;Gu et al., 2013;Huang et al., 1999;Murase, Lantz, & Quinlan, 2017;Pizzorusso et al., 2002;Stephany, Ikrar, Nguyen, Xu, & McGee, 2016;Sugiyama et al., 2008;Tropea et al., 2006). However, they do not account for the translation of brief sensory deprivation into functional changes in circuit connections. ...
Experience-dependent critical period plasticity has been extensively studied in the visual cortex. Monocular deprivation during the critical period affects ocular dominance, limits visual performance, and contributes to the pathological etiology of amblyopia. Neuregulin-1 (NRG1) signaling through its tyrosine kinase receptor ErbB4 is essential for the normal development of the nervous system, and has been linked to neuropsychiatric disorders such as schizophrenia. We discovered recently that NRG1/ErbB4 signaling in PV neurons is critical for the initiation of critical period visual cortical plasticity by controlling excitatory synaptic inputs onto PV neurons and thus PV-cell mediated cortical inhibition that occurs following visual deprivation. Building on this discovery, we review the existing literature of neuregulin signaling in developing and adult cortex, and address the implication of NRG/ErbB4 signaling in visual cortical plasticity at the cellular and circuit levels. NRG-directed research may lead to therapeutic approaches to reactivate plasticity in the adult cortex. This article is protected by copyright. All rights reserved.
... Thus, our study has translational implications for the management of early acquired or congenital deafness (for review, e.g., Kral and Sharma 2012), blindness (for review, e.g., Renier et al. 2014;Nys et al. 2015), and sensory paralysis (for review, e.g., Kaas and Collins 2003;Navarro et al. 2007). Therapeutic approaches that focus on the survival and viability of early multisensory connections at the end of the critical period, for example, by multisensory perceptual training (e.g., Proulx et al. 2014;McGovern et al. 2016), sensory substitution (e.g., Stiles and Shimojo 2015;Maidenbaum et al. 2014), or, though still prospectively, manipulation of the molecular background (e.g., Berardi et al. 2003;Tropea et al. 2009;Hubener and Bonhoeffer 2014), might greatly improve the clinical outcome. ...
The nervous system integrates information from multiple senses. This multisensory integration already occurs in primary sensory cortices via direct thalamocortical and corticocortical connections across modalities. In humans, sensory loss from birth results in functional recruitment of the deprived cortical territory by the spared senses but the underlying circuit changes are not well known. Using tracer injections into primary auditory, somatosensory, and visual cortex within the first postnatal month of life in a rodent model (Mongolian gerbil) we show that multisensory thalamocortical connections emerge before corticocortical connections but mostly disappear during development. Early auditory, somatosensory, or visual deprivation increases multisensory connections via axonal reorganization processes mediated by non-lemniscal thalamic nuclei and the primary areas themselves. Functional single-photon emission computed tomography of regional cerebral blood flow reveals altered stimulus-induced activity and higher functional connectivity specifically between primary areas in deprived animals. Together, we show that intracortical multisensory connections are formed as a consequence of sensory-driven multisensory thalamocortical activity and that spared senses functionally recruit deprived cortical areas by an altered development of sensory thalamocortical and corticocortical connections. The functional–anatomical changes after early sensory deprivation have translational implications for the therapy of developmental hearing loss, blindness, and sensory paralysis and might also underlie developmental synesthesia.
... Dichos autores concluyeron que la plasticidad de la dominancia ocular refleja el dinamismo de las interacciones y la competencia por el espacio sináptico que se da entre los dos ojos. A este respecto, se ha confirmado que durante los periodos críticos, la falta de dominancia ocular y la disminución de actividad visual del ojo privado es irreversible (Berardi, Pizzorusso & Maffei 2000;Berardi, Pizzorusso, Ratto & Maffei 2003). ...
... This synaptotrophic role of neurotrophins results in changes in the balance between exci- tation and inhibition and in the number and activity of synapses ( Singh et al., 2006;Huh et al., 2008). Moreover, neurotrophins have a role regulating discharge properties at the cellular and network levels ( Berardi et al., 2003;Caleo et al., 2003;Luther and Birren, 2009). However, given the multiplicity of pathways and signaling events in the brain, combined with its heteroge- neous synaptic organization, no common rule for neurotro- phin action emerges that could apply to every part of the brain. ...
... Sensory deprivation during a critical period perturbs both the structure [21][22][23] and function [24][25][26][27][28] of the primary visual cortex (V1), such as dark exposure [29] and monocular deprivation [30][31][32]. These two visual deprivation paradigms alter various elements of incoming sensory information in the visual cortex. ...
Visual deprivation during the critical period induces long-lasting changes in cortical circuitry by adaptively modifying neuro-Transmission and synaptic connectivity at synapses. Spike timing-dependent plasticity (STDP) is considered a strong candidate for experience-dependent changes. However, the visual deprivation forms that affect timing-dependent long-Term potentiation(LTP) and long-Term depression(LTD) remain unclear. Here, we demonstrated the temporal window changes of tLTP and tLTD, elicited by coincidental pre-And post-synaptic firing, following different modes of 6-day visual deprivation. Markedly broader temporal windows were found in robust tLTP and tLTD in the V1M of the deprived visual cortex in mice after 6-day MD and DE. The underlying mechanism for the changes seen with visual deprivation in juvenile mice using 6 days of dark exposure or monocular lid suture involves an increased fraction of NR2b-containing NMDAR and the consequent prolongation of NMDAR-mediated response duration. Moreover, a decrease in NR2A protein expression at the synapse is attributable to the reduction of the NR2A/2B ratio in the deprived cortex. © 2017 Guo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
... Much effort has concentrated on the hippocampus, a phylogenetically ancient area of archicortex, which is thought to be involved in the laying down of episodic memory of personal experience and spatial memories. But there has also been progress in defining the molecular bases of synaptic plasticity in developing areas of the neocortex (see Berardi et al, 2003). ...
... In recent years, studies of post-mortem brain tissue from individuals with SCZ have revealed reduced densities of perineuronal nets (PNNs), highly specialized extracellular matrix structures closely associated with inhibitory interneurons 16,17 . PNNs surround the cell body, proximal dendrites, and initial axon segment of the neurons which host them, and are involved in a variety of processes which limit both structural and synaptic plasticity [18][19][20][21][22][23][24][25][26] . Deficits in PNNs are observed in the prefrontal cortex, entorhinal cortex, amygdala, and olfactory epithelium in post-mortem tissue from people with SCZ [27][28][29][30][31] . ...
Maternal infection during pregnancy increases the risk of offspring developing schizophrenia later in life. Similarly, animal models of maternal immune activation (MIA) induce behavioural and anatomical disturbances consistent with a schizophrenia-like phenotype in offspring. Notably, cognitive impairments in tasks dependent on the prefrontal cortex (PFC) are observed in humans with schizophrenia and in offspring after MIA during pregnancy. Recent studies of post-mortem tissue from individuals with schizophrenia revealed deficits in extracellular matrix structures called perineuronal nets (PNNs), particularly in PFC. Given these findings, we examined PNNs over the course of development in a well-characterized rat model of MIA using polyinosinic-polycytidylic acid (polyI:C). We found selective reductions of PNNs in the PFC of polyI:C offspring which did not manifest until early adulthood. These deficits were not associated with changes in parvalbumin cell density, but a decrease in the percentage of parvalbumin cells surrounded by a PNN. Developmental expression of PNNs was also significantly altered in the amygdala of polyI:C offspring. Our results indicate MIA causes region specific developmental abnormalities in PNNs in the PFC of offspring. These findings confirm the polyI:C model replicates neuropathological alterations associated with schizophrenia and may identify novel mechanisms for cognitive and emotional dysfunction in the disorder.
Neuroplasticity refers to the ability of brain circuits to reorganize and change the properties of the network, resulting in alterations in brain function and behavior. It is traditionally believed that neuroplasticity is influenced by external stimuli, learning, and experience. Intriguingly, there is new evidence suggesting that endogenous signals from the body's periphery may play a role. The gut microbiota, a diverse community of microorganisms living in harmony with their host, may be able to influence plasticity through its modulation of the gut-brain axis. Interestingly, the maturation of the gut microbiota coincides with critical periods of neurodevelopment, during which neural circuits are highly plastic and potentially vulnerable. As such, dysbiosis (an imbalance in the gut microbiota composition) during early life may contribute to the disruption of normal developmental trajectories, leading to neurodevelopmental disorders. This review aims to examine the ways in which the gut microbiota can affect neuroplasticity. It will also discuss recent research linking gastrointestinal issues and bacterial dysbiosis to various neurodevelopmental disorders and their potential impact on neurological outcomes.
For medical and fundamental reasons, we need to understand adult brain plasticity at several levels: structural, physiological, and behavioural. Historically, brain plasticity has been mostly investigated by weakening or removing sensory inputs. The visual system has been extensively used because diminishing visual inputs - i.e., visual deprivation-induced plasticity - permits more tractable findings. The present review is centered on the reverse strategy, by imposing a novel stimulus - i.e., adaptation-induced plasticity. Adaptation refers to the constant (milliseconds to hours) presentation of a non-optimal stimulus (adapter) within the receptive field (RF, spatial area that modulates neuronal firing) of the neuron under observation. We specifically focus on how adaptation impacts the tuning of visual neurons with other associated properties. After adaptation, visual cortical neurons respond robustly to the adapter (pre-adaptation it typically evokes feeble responses) by developing alternate tuning curves that outlast the adaptation time. Here, with dendritic structure as foundation, we synthesize a push-pull mechanism of development and acquisition of novel tuning curves following adaptation. We then explain how these changes apply at the global level across different brain regions and species with a short description of underlying neurochemical changes. Finally, we discuss physiopathological consequences and conclude with some gaps and questions that need to be addressed to further comprehend such neuroplasticity.
Anger has always been included in the repertoire of basic emotions. In 5- to 12-month-old infants viewing facial expressions of happiness, fear, and anger, the right fusiform face area, which is related to N290 event-related potentials (ERP) component, was found to be larger in amplitude in response to fearful and happy faces than to angry ones, while the posterior cingulate cortex/precuneus, which is related to the P400 and the Nc ERP components, was found to be larger in response to angry faces than to happy and fearful ones. These effects emerged at 5 months and disappeared at 12 months. This evidence may suggest a sensitive period related to the development of safety. According to polyvagal theory, the development of the feelings of safety is accomplished through neuroception, a neural reflexive mechanism, capable of distinguishing between safe, dangerous, and life-threatening features. A neuroception of safety supports the ventral vagal complex (VVC) and the social engagement system in safe contexts; alternatively, a neuroception of danger, or life threat, favors recruitment of the sympathetic nervous system (SNS) or the dorsal vagal complex (DVC), respectively. Unsafety detection may preferentially promote the emergence of SNS self-protective strategies related to anger to avoid the predominance of DVC self-protective strategies related to fear. Assessment of feelings of safety through neurophysiologically-informed psychometric tools is recommended, and the experience of safety, psychotherapy, and drugs may promote the decrease of unmyelinated-to-myelinated cardioinhibitory fiber ratio of the parasympathetic nervous system and the emergence of VVC, through a process of activity-dependent myelination.
Purpose:
Synaptosomal actin dynamics are essential for synaptic structural stability. Whether actin dynamics are involved in structural and functional synaptic plasticity within the primary visual cortex (V1) or behavioral visual acuity in rats has still not been thoroughly investigated.
Methods:
Synaptosome preparation and western blot analysis were used to analyze synaptosomal actin dynamics. Transmission electron microscopy was used to detect synaptic density and mitochondrial area alterations. A visual water maze task was applied to assess behavioral visual acuity. Microinjection of the actin polymerization inhibitor or stabilizer detected the effect of actin dynamics on visual function.
Results:
Actin dynamics, the mitochondrial area, and synaptic density within the area of V1 are increased during the critical period for the development of binocularity. Microinjection of the actin polymerization inhibitor cytochalasin D into the V1 decreased the mitochondrial area, synaptic density, and behavioral visual acuity. Long-term monocular deprivation reduced actin dynamics, the mitochondrial area, and synaptic density within the V1 contralateral to the deprived eye compared with those ipsilateral to the deprived eye and impaired visual acuity in the amblyopic eye. In addition, the mitochondrial area, synaptic density, and behavioral visual acuity were improved by stabilization of actin polymerization by jasplakinolide microinjection.
Conclusions:
During the critical period of visual development of binocularity, synaptosomal actin dynamics regulate synaptic structure and function and play roles in behavioral visual acuity in rats.
Glutamate is an amino acid used in biochemical pathways of all cells, but it is also packaged and released as a neurotransmitter from many neurons in the vertebrate central nervous system (CNS). Glutamate is released at specific junctions, synapses, between a glutamate‐releasing neuron and target neurons that express surface receptors for glutamate. Most neurons in the vertebrate CNS, even if they themselves do not use glutamate as a neurotransmitter, have glutamate receptors. Glutamate receptors initiate electrical and biochemical signals in the target cell and can induce changes in strength of signalling that neuroscientists believe underlie the ability of thoughts and behaviours to change with experience. Glutamate receptors fall into two classes: ligand‐gated ion channels (ionotropic) and G protein coupled (metabotropic). In addition to propagating and modulating normal electrical signalling, glutamate receptors, activated excessively, can cause neurotoxicity in disease states.
Key Concepts
• Glutamate is used as a neurotransmitter at the majority of synapses in the vertebrate CNS.
• Glutamate typically has an excitatory action on target neurons, increasing the probability of electrical impulse firing in the target.
• Glutamate acts through G protein‐coupled receptors and through ligand‐gated ion channels.
• Glutamate synapses exhibit remarkable plasticity (malleability) that may play an important role in memory formation.
• In excess glutamate can be neurotoxic, acting through the same glutamate receptors that mediate normal signalling.
Vision loss has long since been considered irreversible after a critical period; however, there is potential to restore limited vision, even in adulthood. This phenomenon is particularly pronounced following complete loss of vision in the dominant eye. Adult neural cell adhesion molecule (NCAM) knockout mice have an age-related impairment of visual acuity. The underlying cause of early deterioration in visual function remains unknown. Polysialylated (PSA) NCAM is involved in different forms of neural plasticity in the adult brain, raising the possibility that NCAM plays a role in the plasticity of the visual cortex, and therefore, in visual ability. Here, we examined whether PSA-NCAM is required for visual cortical plasticity in adult C57Bl/6J mice following deafferentation and long-term monocular deprivation. Our results show that elevated PSA in the contralateral visual cortex of the reopened eye is accompanied by changes in other markers of neural plasticity: increased brain-derived neurotrophic factor (BDNF) levels and degradation of perineuronal nets (PNNs). The removal of PSA-NCAM in the visual cortex of these mice reduced BDNF expression, decreased PNN degradation, and resulted in impaired recovery of visual acuity after optic nerve transection and chronic monocular deprivation. Collectively, our results demonstrate that PSA-NCAM is necessary for the reactivation of visual cortical plasticity and recovery of visual function in adult mice. It also offers a potential molecular target for the therapeutic treatment of cortically based visual impairments.
Mice and rats have become popular models of visual functions because of the powerful experimental approaches that these species afford in the study of brain processes at the molecular, synaptic and circuitry level. To fully exploit this potential, the application of cutting-edge tools to record and manipulate neuronal activity in in vivo (such as high-resolution two-photon imaging and optogenetics) needs to be combined with the quantitative analysis of rodent visual behaviour. In this chapter, we provide a critical and extensive overview of the methodological approaches that have been applied to investigate visual cognition of laboratory mice and rats. The scope of our survey is very broad, encompassing studies targeting a variety of visual perceptual and memory functions, such as shape processing, object recognition and memory, spatial navigation and innate visually driven responses. The spectrum of behavioural rigs and experimental designs covered by our review is similarly, large, including tests of spontaneous object recognition, several variants of Go/No-Go and two-alternative forced choice tasks, as well as recent implementations of the latter in virtual visual environments. Finally, we also describe the application of advanced psychophysical procedures, such as visual priming paradigms and classification image approaches, to the study of rodent visual perception. As a result, this chapter provides an exhaustive guide for those vision scientists that are interested in dissecting the neuronal processing underlying complex visual behaviours using the simple, yet powerful, brains of mice and rats.
Schizophrenia is associated with core deficits in cognitive abilities and impaired functioning of the newly evolved prefrontal association cortex (PFC). In particular, neuropathological studies of schizophrenia have found selective atrophy of the pyramidal cell microcircuits in deep layer III of the dorsolateral PFC (dlPFC), and compensatory weakening of related GABAergic interneurons. Studies in monkeys have shown that recurrent excitation in these layer III microcircuits generates the precisely patterned, persistent firing needed for working memory and abstract thought. Importantly, excitatory synapses on layer III spines are uniquely regulated at the molecular level in ways that may render them particularly vulnerable to genetic and/or environmental insults. Glutamate actions are remarkably dependent on cholinergic stimulation, and there are inherent mechanisms to rapidly weaken connectivity, e.g. during stress. In particular, feedforward cyclic adenosine monophosphate (cAMP)-calcium signaling rapidly weakens network connectivity and neuronal firing by opening nearby potassium channels. Many mechanisms that regulate this process are reduced in schizophrenia, and/or associated with genetic insults. Current data suggest that there are “dual hits” to layer III dlPFC circuits: initial insults to connectivity during the perinatal period due to genetic errors and/or inflammatory insults that predispose the cortex to atrophy, followed by a second wave of cortical loss during adolescence, e.g. driven by stress, at the descent into illness. The unique molecular regulation of layer III circuits may provide a nexus where inflammation disinhibits the neuronal response to stress. Understanding these mechanisms may help to illuminate dlPFC susceptibility in schizophrenia, and provide insights for novel therapeutic targets.
The partial recovery that can occur after a stroke has been attributed to structural and functional plasticity that compensate for damage and lost functions. This plasticity is thought to be limited in part by the presence of growth inhibitors in the central nervous system. Blocking or reducing signals from inhibitors of axonal sprouting such as Nogo and chondroitin sulfate proteoglycans (CSPGs) increases post-stroke axonal sprouting and improves recovery. We previously identified the transcription factor SOX9 as a key up-regulator of CSPG production and demonstrated that conditional Sox9 ablation leads to increased axonal sprouting and improved recovery after spinal cord injury. In the present study we evaluate the effect of conditional Sox9 ablation in a transient middle cerebral artery occlusion (MCAO) model of stroke. We demonstrate that conditional Sox9 ablation leads to reduced CSPG levels, increased tissue sparing and improved post-stroke neurological recovery. Anterograde tract tracing studies demonstrate that in the Sox9 conditional knockout mice corticorubral and corticospinal projections from the contralateral, uninjured cortex increase projections to targets in the midbrain and spinal cord denervated by the injury. These results suggest that targeting SOX9 is a viable strategy to promote reparative axonal sprouting, neuroprotection and recovery after stroke.
Nitric oxide (NO) and calcium-binding proteins occur in various types of cells in the central nervous system. They are important signaling and calcium buffering molecules, respectively. In the present study, using immunocytochemistry we examined the distribution and the co-localization pattern of neurons containing neuronal nitric oxide synthase (nNOS) and parvalbumin in the visual cortex of hamster. The overall number of parvalbumin-immunoreactive (IR) neurons was 17 times higher than that of the nNOS-IR neurons in the hamster visual cortex. The highest differences were found in layer V, where parvalbumin-IR neurons were 54.7 times more abundant than nNOS-IR neurons. Many nNOS- and parvalbumin-IR neurons were similar in size, shape, and manner of distribution in the visual cortex. However, two-color immunofluorescence revealed that no neurons in the hamster visual cortex expressed both nNOS and parvalbumin. The present results indicate that there are subtle species differences in the co-localization pattern between nNOS and calcium-binding proteins. The present results also suggest not only the heterogeneity and functional diversity of nNOS-IRneurons in the visual cortex, but also the importance of understanding animal diversity
Until recently most researches on myopia mechanisms have mainly been focused on the eye ball and few investigations were explored on the upper visual pathway, such as the visual cortex. The roles of gamma-aminobutyric acid (GABA) in the retinal and in the upper visual pathway are inter-correlated. As the retinal glutamate decarboxylase (GAD), GABA, and the mRNA levels of GABA receptors increased during the concave lens induced myopia formation, however, whether GABA alterations also occurred in the visual cortex during the concave lens induction is still unknown. In the present study, using HPLC, Enzyme-Linked Immunosorbent Assay (ELISA) and Real-Time Quantitative-PCR (RT-PCR) methods, we observed the changing trends of GABA, glutamate decarboxylase (GAD), and GABA receptors in the visual cortex of concave lens-induced myopic guinea pigs. Similar to the changing patterns of retinal GABA, the concentrations of GAD, GABA and the mRNA levels of GABA receptors in the visual cortex also increased. These results indicate that the exploration on myopia mechanisms should possibly be investigated on the whole visual pathway and the detailed significance of cortical GABA alterations needs further investigation.
Neural plasticity is the ability of neural circuits to reorganize structurally and functionally in response to environmental stimuli. Plasticity is particularly high during developmental time windows called critical periods (CPs), when experience exerts a key role in regulating neural development and the maturation of specific behavioral traits. One classic experimental approach in the field of developmental neural plasticity is that of assessing the effects of a reduction or alteration in the input activity to a neural circuit, with the visual system emerging as the paradigmatic model thanks to widely investigated methodologies such as dark-rearing and monocular vision deprivation. A second major approach is that of increasing and optimizing levels of experience, a framework best represented by the so-called environmental enrichment (EE) model, which consists in a marked increment of motor, social and sensory stimulation obtained by rearing animals in large and highly attractive cages. Recently, we introduced a new experimental avenue in which these two approaches have been combined together, allowing us to probe experience-dependent plasticity with EE and to use manipulations of visual experience combined with EE to unravel previously unknown molecular mechanisms underlying cortical plasticity. This chapter mostly aims at reviewing this recent work, focusing on the effects of EE in promoting central nervous system development and in reopening neural plasticity windows in the adult brain. Special emphasis will be given to the remarkable ability of EE to modulate neural plasticity brakes, such as the excitation/inhibition balance, and to favor functional recovery from pathological states of severe brain disability, such as those associated with Down syndrome.
Background:
The neuropsychological literature on preterm-born children with spastic diplegia due to periventricular leukomalacia is convergent in reporting deficits in non-verbal intelligence and in visuo-spatial abilities. Nevertheless, other cognitive functions have found to be impaired, but data are scant and not correlated with neuroimaging findings.
Aims:
This study analyzes the neuropsychological strengths and weaknesses in preterm-born children with spastic diplegia (pSD) and their relationships with neuroanatomical findings, investigated by a novel scale for MRI classification.
Methods and procedures:
Nineteen children with pSD, mild to moderate upper limb impairment and Verbal IQ>80, and 38 normal controls were evaluated with a comprehensive neuropsychological battery (NEPSY-II), assessing Attention/Executive Functioning, Language, Memory, Sensorimotor, Social Perception and Visuospatial Processing domains. The MRIs were quantitatively scored for lesion severity.
Outcomes and results:
The results showed that, beyond core visuo-spatial and sensory-motor deficits, impairments in attention and executive functions were present in more than half of the sample, particularly in children with damage to the anterior corpus callosum.
Conclusions and implications:
The findings are discussed in terms of clinical and rehabilitative implications tailored for pSD subgroups diversified for neuropsychological and neuroanatomical characteristics.
Perceptual learning is considered a potential treatment for amblyopia even in adult patients who have progressed beyond the critical period of visual development because adult amblyopes retain sufficient visual plasticity. When perceptual learning is performed with the correction of high-order aberrations (HOAs), a greater degree of neural plasticity is present in normal adults and those with highly aberrated keratoconic eyes. Because amblyopic eyes show more severe HOAs than normal eyes, it is interesting to study the effects of HOA-corrected visual perceptual learning in amblyopia. In the present study, we trained twenty-six older child and adult anisometropic amblyopes while their HOAs were corrected using a real-time closed-loop adaptive optics perceptual learning system (AOPL). We found that adaptive optics (AO) correction improved the modulation transfer functions (MTFs) and contrast sensitivity functions (CSFs) of older children and adults with anisometropic amblyopia. When perceptual learning was performed with AO correction of the ocular HOAs, the improvements in visual function were not only demonstrated in the condition with AO correction but were also maintained in the condition without AO correction. Additionally, the learning effect with AO correction was transferred to the untrained visual acuity and fellow eyes in the condition without AO correction.
Specific patterns of neural impulses regulate genes controlling nervous system development and plasticity, but it is not known how intracellular signaling cascades and transcriptional activa- tion mechanisms can regulate specific genes in response to specific patterns of action potentials. Studies using electrical stimulation of mouse dorsal root ganglion neurons in culture show that the temporal dynamics of intracellular signaling path- ways are an important factor. Expression of c-fos varied in- versely with the interval between repeated bursts of action potentials. Transcription was not dependent on a large or sus- tained increase in intracellular Ca 21, and high Ca 21 levels separated by long interburst intervals (5 min) produced minimal increases in c-fos expression. Levels of the transcription factor cAMP-responsive element binding protein (CREB), phosphory- lated at Ser-133, increased rapidly in response to brief action potential stimulation but remained at high levels several min- utes after an action potential burst. These kinetics limited the fidelity with which P-CREB could follow different patterns of action potentials, and P-CREB levels were not well correlated with c-fos expression. The extracellular-regulated kinase (ERK) mitogen-activated protein kinases (MAPK) also were stimulated by action potentials of appropriate temporal patterns. Bursts of action potentials separated by long intervals (5 min) did not activate MAPK effectively, but they did increase CREB phos- phorylation. This was a consequence of the more rapid de- phosphorylation of MAPK in comparison to CREB. High ex- pression of c-fos was dependent on the combined activation of the MAPK pathway and phosphorylation of CREB. These ob- servations show that temporal features of action potentials (and associated Ca 21 transients) regulate expression of neuronal
The cAMP responsive element binding protein (CREB) is a nuclear protein that modulates the transcription of genes with cAMP responsive elements in their promoters. Increases in the concentration of either calcium or cAMP can trigger the phosphorylation and activation of CREB. This transcription factor is a component of intracellular signaling events that regulate a wide range of biological functions, from spermatogenesis to circadian rhythms and memory. Here we review the key features of CREB-dependent transcription, as well as the involvement of CREB in memory formation. Evidence from Aplysia, Drosophila, mice, and rats shows that CREB-dependent transcription is required for the cellular events underlying long-term but not short-term memory. While the work in Aplysia and Drosophila only involved CREB function in very simple forms of conditioning, genetic and pharmacological studies in mice and rats demonstrate that CREB is required for a variety of complex forms of memory, including spatial and social learning, thus indicating that CREB may be a universal modulator of processes required for memory formation.
Do changes in neuronal structure underlie cortical plasticity? Here we used time-lapse two-photon microscopy of pyramidal neurons in layer 2/3 of developing rat barrel cortex to image the structural dynamics of dendritic spines and filopodia. We found that these protrusions were highly motile: spines and filopodia appeared, disappeared or changed shape over tens of minutes. To test whether sensory experience drives this motility we trimmed whiskers one to three days before imaging. Sensory deprivation markedly (approximately 40%) reduced protrusive motility in deprived regions of the barrel cortex during a critical period around postnatal days (P)11-13, but had no effect in younger (P8-10) or older (P14-16) animals. Unexpectedly, whisker trimming did not change the density, length or shape of spines and filopodia. However, sensory deprivation during the critical period degraded the tuning of layer 2/3 receptive fields. Thus sensory experience drives structural plasticity in dendrites, which may underlie the reorganization of neural circuits.
To assess the possibility that NMDA receptors play a special role in visual cortical plasticity, the selective antagonist 2-amino-5-phosphonovaleric acid (APV) was continuously infused into the striate cortex of kittens as the visual environment was manipulated during the critical period. The cortex was studied using single-unit recording from sites between 3 and 6 mm from the infusion cannulae. One week of D,L-APV infusion coincident with monocular deprivation or "reverse suture" produced a concentration-dependent increase in the percentage of neurons that (1) lacked normal orientation selectivity and (2) were responsive to stimulation of the deprived eye. These effects outlasted the presence of the drug in the tissue. APV treatment also prevented the acquisition of selectivity and visual responsiveness that normally results from monocular visual experience after dark-rearing. Lasting effects of chronic APV infusion were not observed in adult striate cortex. The effects of APV on kitten striate cortex depended on the presence of the D stereoisomer as infusion of L-APV was without effect. Estimates of extracellular concentration using 3H-APV indicated that significant effects could be obtained with concentrations as low as 20 microM D,L-APV. Recordings from units during infusion indicated that visual responses were reduced by APV. Nonetheless, a normal percentage of visually responsive neurons was found at sites greater than or equal to 3 mm from the infusion cannula. There was no evidence that chronic APV infusion affected the sampling frequency of recorded neurons or disrupted cytoarchitecture at the sites further than 3 mm from the infusion cannula. Taken together, the data indicate that the effects of APV on kitten striate cortex are likely due specifically to the blockade of NMDA receptors. These data are considered in relation to several hypotheses concerning the role of NMDA receptors in the experience-dependent development of striate cortex.
The monoclonal antibody Cat-301, generated against cat spinal cord (McKay and Hockfield, 1982), recognizes a surface-associated antigen that, in the cat lateral geniculate nucleus (LGN), is selectively expressed on Y-cells (Hockfield et al., 1983; Hendry et al., 1984; Sur et al., 1984). We now report that the antigen recognized by Cat-301 appears late in development, along a time course similar to that described for the maturation of the physiological properties of Y-cells in the LGN, and that its expression is sharply reduced by monocular lid suture or dark-rearing from birth, 2 visual deprivation procedures that lead to a reduction in the proportion of Y-cells recorded physiologically in the LGN (Sherman et al., 1972; Kratz et al., 1979; reviewed in Sherman and Spear, 1982). Monocular lid suture in the adult has no effect on Cat-301 antigen levels or, as previously reported (Sherman et al., 1972), on the proportion of physiologically recorded Y-cells. In addition, reversing the monocular deprivation in adulthood by opening the neonatally sutured eye and suturing closed the previously normal eye for 6 months restores neither normal levels of Cat-301 labeling nor, as previously reported (Geisert et al., 1982), the proportion of recordable Y-cells. The development of Cat-301 immunoreactivity thus parallels the development of LGN Y-cell physiology. The relative reduction in levels of immunoreactivity consequent to neonatal, but not adult, visual deprivation shows that Cat-301 antigen expression does not simply reflect the level of visually evoked electrical activity in the LGN, but rather reflects a process that depends on the nature of visual experience early in life.(ABSTRACT TRUNCATED AT 250 WORDS)
Several studies have suggested that the function of glutamate receptor channels can be regulated by protein phosphorylation. Furthermore, a basal level of phosphorylation may be necessary to maintain receptor function. Little is known, however, about the phosphorylation state of glutamate receptor channels in neurons and how it is regulated by synaptic activity. In this study, we have investigated the phosphorylation of the AMPA-preferring glutamate receptor subunit GluR1 in cortical neurons in primary culture. These neurons elaborate extensive processes, form functional synapses, and exhibit spontaneous 4-8 sec bursts of synaptic activity every 15-20 sec. In cultures in which this synaptic activity was suppressed by tetrodotoxin and MK-801, the GluR1 protein was phosphorylated on serine residues within a single tryptic phosphopeptide, as determined by phosphoamino acid analysis and phosphopeptide mapping. This same peptide was basally phosphorylated in recombinant GluR1 receptors transiently expressed in human embryonal kidney 293 cells. Treatment of these synaptically inactive cortical neurons with the adenylyl cyclase activator forskolin resulted in a robust increase in phosphorylation on serine residues on a phosphopeptide distinct from the basally phosphorylated peptide. Again, this same phosphopeptide was observed in recombinant GluR1 receptors isolated from 293 cells coexpressing the catalytic subunit of cAMP-dependent protein kinase. Spontaneous synaptic activity in cultures of cortical neurons resulted in a consistent, rapid (within 10-30 sec) increase in phosphorylation on serine and threonine residues. Interestingly, these phosphopeptides were also phosphorylated when neurons from inactive cultures were stimulated with phorbol esters, which activate protein kinase C. These results indicate that AMPA receptors containing the GluR1 subunit may be regulated by extracellular signals working through the cAMP second messenger system as well as by synaptic activity, possibly acting through protein kinase C. Such regulation by protein phosphorylation may be involved in short-term changes in synaptic efficacy thought to involve the functional modulation of AMPA receptors.
Phosphorylation of CREB (cyclic AMP [cAMP]- response element [CRE]-binding protein) by cAMP-dependent protein kinase (PKA)
leads to the activation of many promoters containing CREs. In neurons and other cell types, CREB phosphorylation and activation
of CRE-containing promoters can occur in response to elevated intracellular Ca2+. In cultured cells that normally lack this
Ca2+ responsiveness, we confer Ca(2+)-mediated activation of a CRE-containing promoter by introducing an expression vector
for Ca2+/calmodulin-dependent protein kinase type IV (CaMKIV). Activation could also be mediated directly by a constitutively
active form of CaMKIV which is Ca2+ independent. The CaMKIV-mediated gene induction requires the activity of CREB/ATF family
members but is independent of PKA activity. In contrast, transient expression of either a constitutively active or wild-type
Ca2+/calmodulin-dependent protein kinase type II (CaMKII) fails to mediate the transactivation of the same CRE-containing
reporter gene. Examination of the subcellular distribution of transiently expressed CaMKIV and CaMKII reveals that only CaMKIV
enters the nucleus. Our results demonstrate that CaMKIV, which is expressed in neuronal, reproductive, and lymphoid tissues,
may act as a mediator of Ca(2+)-dependent gene induction.
Exogenous supply of nerve growth factor (NGF) prevents the effects of monocular deprivation. This suggests that visual afferents may be competing for an endogenous neurotrophic factor, related to NGF, whose production by postsynaptic cells depends on the activity of afferent fibers. To test the hypothesis that endogenous NGF may play a role in the functional and anatomical development of the rat geniculo cortical system, the physiological action of NGF in the rat visual system was antagonized by using two independent monoclonal antibodies which neutralize NGF (alpha D11 and 4C8). To provide a continuous supply of antibodies during the period of visual cortical plasticity, alpha D11 or 4C8 antibody-producing hybridoma cells were implanted in the lateral ventricle of rats at postnatal day 15. This resulted in dramatic alterations of two of the most important parameters characterizing the functional development of the visual system, namely, visual acuity and binocularity of cortical neurons and in shrinkage of cells in the lateral geniculate nucleus. This demonstrates that the action of endogenous NGF is necessary for the normal functional and anatomical development of the geniculocortical system.
The ability of neurotrophins to modulate the survival and differentiation of neuronal populations involves the Trk/MAP (mitogen-activated protein kinase) kinase signaling pathway. More recently, neurotrophins have also been shown to regulate synaptic transmission. The synapsins are a family of neuron-specific phosphoproteins that play a role in regulation of neurotransmitter release, in axonal elongation, and in formation and maintenance of synaptic contacts. We report here that synapsin I is a downstream effector for the neurotrophin/Trk/MAP kinase cascade. Using purified components, we show that MAP kinase stoichiometrically phosphorylated synapsin I at three sites (Ser-62, Ser-67, and Ser-549). Phosphorylation of these sites was detected in rat brain homogenates, in cultured cerebrocortical neurons, and in isolated presynaptic terminals. Brain-derived neurotrophic factor and nerve growth factor upregulated phosphorylation of synapsin I at MAP kinase-dependent sites in intact cerebrocortical neurons and PC12 cells, respectively, while KCl- induced depolarization of cultured neurons decreased the phosphorylation state at these sites. MAP kinase-dependent phosphorylation of synapsin I significantly reduced its ability to promote G-actin polymerization and to bundle actin filaments. The results suggest that MAP kinase-dependent phosphorylation of synapsin I may contribute to the modulation of synaptic plasticity by neurotrophins and by other signaling pathways that converge at the level of MAP kinase activation.
Monoclonal antibody Cat-301 recognizes a chondroitin sulfate proteoglycan (CSPG) expressed on the extracellular surface of cell bodies and proximal dendrites of specific subsets of neurons in many areas of the mammalian CNS, including the cat visual cortex. The Cat-301 CSPG is first detected at the close of the critical period in development, a period during which the pattern of neuronal activity determines the mature synaptic circuitry and neuronal phenotype. In the cat visual cortex, dark-rearing from birth prolongs the duration of the critical period and attenuates the expression of the Cat-301 antigen, implicating the Cat-301 CSPG in the cellular mechanisms that terminate the period of synaptic plasticity. Because the Cat-301 antigen is expressed on only a limited subset of neurons, we have further examined the molecular heterogeneity among neuronal cell-surface CSPGs and have asked (1) whether other neuronal subsets carry distinct CSPGs and (2) whether the activity-dependent expression of the Cat-301 CSPG is a property generalizable to related cell-surface CSPGs. Here, we report two new monoclonal antibodies, Cat-315 and Cat-316, which together with Cat-301 define a family of at least seven related yet distinct CSPGs. These three antibodies define nonidentical subsets of neurons in the cat visual cortex. The expression of normal levels of these CSPGs is reduced by dark-rearing. Together, these data show that the family of cell-surface CSPGs is molecularly diverse, that different sets of neurons express distinct complements of cell-surface antigens, and that the regulation of CSPG expression by activity may be a general feature of neuronal cell-surface CSPGs.
Long-term potentiation (LTP) at the Schaffer collateral–CA1 synapse involves interacting signaling components, including calcium
(Ca2+)/calmodulin–dependent protein kinase II (CaMKII) and cyclic adenosine monophosphate (cAMP) pathways. Postsynaptic injection
of thiophosphorylated inhibitor-1 protein, a specific inhibitor of protein phosphatase–1 (PP1), substituted for cAMP pathway
activation in LTP. Stimulation that induced LTP triggered cAMP-dependent phosphorylation of endogenous inhibitor-1 and a decrease
in PP1 activity. This stimulation also increased phosphorylation of CaMKII at Thr286 and Ca2+-independent CaMKII activity in a cAMP-dependent manner. The blockade of LTP by a CaMKII inhibitor was not overcome by thiophosphorylated
inhibitor-1. Thus, the cAMP pathway uses PP1 to gate CaMKII signaling in LTP.
Sensory experience in early life shapes the mammalian brain. An impairment in the activity-dependent refinement of functional
connections within developing visual cortex was identified here in a mouse model. Gene-targeted disruption of one isoform
of glutamic acid decarboxylase prevented the competitive loss of responsiveness to an eye briefly deprived of vision, without
affecting cooperative mechanisms of synapse modification in vitro. Selective, use-dependent enhancement of fast intracortical
inhibitory transmission with benzodiazepines restored plasticity in vivo, rescuing the genetic defect. Specific networks of
inhibitory interneurons intrinsic to visual cortex may detect perturbations in sensory input to drive experience-dependent
plasticity during development.
Kittens were given intramuscular injections of the N-methyl--aspartate (NMDA) antagonist MK-801 twice daily (morning and midday) during the peak of the period of susceptibility for ocular dominance changes. They were then exposed to light with one eye closed for 4 h after each injection. The ocular dominance of these kittens was shifted significantly less than that of kittens injected with saline and exposed to light over the same period at the same age. After recording a sample of cells for an ocular dominance histogram, the kittens were injected with the same dose of MK-801 that was used during rearing to observe its effect on the activity of single cells in the visual cortex. In the majority of cells (7/13) there was no significant change in activity. Positive evidence for a reduction in activity was seen in only a minority (3/13) of cells. In a separate series of experiments, dose-response curves were measured for cells in the visual cortex in response to iontophoresis of NMDA or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and the effect of an injection of MK-801 on these curves was measured. MK-801, at doses similar to those used in the ocular dominance experiments, had a significant effect on the dose-response curves for NMDA, but little effect on the dose-response curves for AMPA, or the visual responses of the cells. We conclude that ocular dominance shifts can be reduced significantly by a treatment that has little effect on the level of activity of cells in the visual cortex but does specifically affect the responses of the cells to NMDA as opposed to the responses to AMPA.
The extracellular matrix glycoprotein tenascin-R (TN-R), colocalizing with hyaluronan, phosphacan, and aggregating chondroitin sulphate proteoglycans in the white and grey matter, is accumulated in perineuronal nets that surround different types of neurons in many brain regions. To characterize the role of TN-R in the formation of perineuronal nets, we studied their postnatal development in wild-type mice and in a TN-R knock-out mutant by using the lectin Wisteria floribunda agglutinin and an antibody to nonspecified chondroitin sulphate proteoglycans as established cytochemical markers. We detected the matrix components TN-R, hyaluronan, phosphacan, neurocan, and brevican in the perineuronal nets of cortical and subcortical regions. In wild-type mice, lectin-stained, immature perineuronal nets were first seen on postnatal day 4 in the brainstem and on day 14 in the cerebral cortex. The staining intensity of these nets for TN-R, hyaluronan, phosphacan, neurocan, and brevican was extremely weak or not distinguishable from that of the surrounding neuropil. However, all markers showed an increase in staining intensity of perineuronal nets reaching maximal levels between postnatal days 21 and 40. In TN-R-deficient animals, the perineuronal nets tended to show a granular component within their lattice-like structure at early stages of development. Additionally, the staining intensity in perineuronal nets was reduced for brevican, extremely low for hyaluronan and neurocan, and virtually no immunoreactivity was detectable for phosphacan. The granular configuration of perineuronal nets became more predominant with advancing age of the mutant animals, indicating the continued abnormal aggregation of chondroitin sulphate proteoglycans complexed with hyaluronan. As shown by electron microscopy in the cerebral cortex, the disruption of perineuronal nets was not accompanied by apparent changes in the synaptic structure on net-bearing neurons. The regional distribution patterns and the temporal course of development of perineuronal nets were not obviously changed in the mutant. We conclude that the lack of TN-R initially and continuously disturbs the molecular scaffolding of extracellular matrix components in perineuronal nets. This may interfere with the development of the specific micromilieu of the ensheathed neurons and adjacent glial cells and may also permanently change their functional properties. J. Comp. Neurol. 428:616–629, 2000. © 2000 Wiley-Liss, Inc.
Sensory experience in early life shapes the mammalian brain. An impairment in the activity-dependent refinement of functional connections within developing visual cortex was identified here in a mouse model. Gene-targeted disruption of one isoform of glutamic acid decarboxylase prevented the competitive loss of responsiveness to an eye briefly deprived of vision, without affecting cooperative mechanisms of synapse modification in vitro. Selective, use-dependent enhancement of fast intracortical inhibitory transmission with benzodiazepines restored plasticity in vivo, rescuing the genetic defect. Specific networks of inhibitory interneurons intrinsic to visual cortex may detect perturbations in sensory input to drive experience-dependent plasticity during development
Neurotrophins strongly affect visual system development and plasticity. However, the mode of delivery and targets of neurotrophin action are still under debate. For instance, cortical NT-4/5 (neurotrophin 4/5; Ntf4/5) was shown to rescue lateral geniculate nucleus (LGN) neurons from monocular deprivation-induced atrophy suggesting a retrograde action on thalamic afferents. It is still unclear whether LGN neurons respond to NT-4/5 and other neurotrophins during development in animals with normal vision. We now show that infusions of NT-4/5 and NGF (nerve growth factor) into visual cortex at the onset and the peak of the critical period accelerated LGN neuron growth. BDNF (brain-derived neurotrophic factor) was ineffective. The effects of neurotrophin on LGN development were clearly dissociated from the effects at cortical level because soma growth of cortical layer IV and VI neurons was strongly promoted by BDNF. NT-4/5 was only effective at the onset, but no longer at the peak of the critical period suggesting a switch in neurotrophin dependency for these cortical cell classes. To dissociate retrograde and anterograde effects of the TrkB ligands, we analyzed the stratum griseum superficiale (SGS) of the superior colliculus, a target of visual cortical efferents. Indeed, TrkB-expressing inhibitory SGS neurons responded to cortical NT-4/5 infusion with somatic growth. Strikingly, the TrkB-expressing excitatory tectothalamic calbindin neurons in the SGS did not respond. This demonstrated for the first time a selective cell type-specific anterograde action of NT-4/5 and suggested for the LGN that anterograde as well as retrograde effects contribute to soma size regulation. Strikingly, cortical infusion of the cytokine LIF, which affects development of visual cortex neurochemical architecture, transiently inhibited growth of neurons in LGN, cortical layer IV and VI and SGS. In summary, the study presents three important results. First, central neurons regulate soma size development in an age-and ligand-specific fashion. Second, NT-4/5 and NGF accelerate LGN development in rats with normal vision while LIF delays growth. Third, anterogradely transported NT-4/5 effectively promotes neuronal maturation. These differential actions on subcortical neurons may contribute to the different effects of neurotrophins on visual system development and plasticity.
gamma-Aminobutyric acid_A (GABA_A) receptors are ligand-gated ion channels that mediate inhibitory synaptic transmission in the central nervous system. The role of protein phosphorylation in the modulation of GABA_A receptor function was examined with cells transiently transfected with GABA_A receptor subunits. GABA_A receptors consisting of the alpha_1 and beta_1 or the alpha_1, beta_1, and gamma_2 subunits were directly phosphorylated on the beta_1 subunit by adenosine 3',5'-monophosphate (cAMP)-dependent protein kinase (PKA). The phosphorylation decreased the amplitude of the GABA response of both receptor types and the extent of rapid desensitization of the GABA_A receptor that consisted of the alpha_1 and beta_1 subunits. Site-specific mutagenesis of the serine residue phosphorylated by PKA completely eliminated the PKA phosphorylation and modulation of the GABA_A receptor. In primary embryonic rat neuronal cell cultures, a similar regulation of GABA_A receptors by PKA was observed. These results demonstrate that the GABA_A receptor is directly modulated by protein phosphorylation and suggest that neurotransmitters or neuropeptides that regulate intracellular cAMP levels may modulate the responses of neurons to GABA and consequently have profound effects on synaptic excitability.
Despite considerable evidence that neuronal activity influences the organization and function of circuits in the developing and adult brain, the molecular signals that translate activity into structural and functional changes in connections remain largely obscure. This review discusses the evidence implicating neurotrophins as molecular mediators of synaptic and morphological plasticity. Neurotrophins are attractive candidates for these roles because they and their receptors are expressed in areas of the brain that undergo plasticity, activity can regulate their levels and secretion, and they regulate both synaptic transmission and neuronal growth. Although numerous experiments show demonstrable effects of neurotrophins on synaptic plasticity, the rules and mechanisms by which they exert their effects remain intriguingly elusive.
The extracellular matrix glycoprotein tenascin-R (TN-R), colocalizing with hyaluronan, phosphacan, and aggregating chondroitin sulphate proteoglycans in the white and grey matter, is accumulated in perineuronal nets that surround different types of neurons in many brain regions. To characterize the role of TN-R in the formation of perineuronal nets, we studied their postnatal development in wild-type mice and in a TN-R knock-out mutant by using the lectin Wisteria floribunda agglutinin and an antibody to nonspecified chondroitin sulphate proteoglycans as established cytochemical markers. We detected the matrix components TN-R, hyaluronan, phosphacan, neurocan, and brevican in the perineuronal nets of cortical and subcortical regions. In wild-type mice, lectin-stained, immature perineuronal nets were first seen on postnatal day 4 in the brainstem and on day 14 in the cerebral cortex. The staining intensity of these nets for TN-R, hyaluronan, phosphacan, neurocan, and brevican was extremely weak or not distinguishable from that of the surrounding neuropil. However, all markers showed an increase in staining intensity of perineuronal nets reaching maximal levels between postnatal days 21 and 40. In TN-R-deficient animals, the perineuronal nets tended to show a granular component within their lattice-like structure at early stages of development. Additionally, the staining intensity in perineuronal nets was reduced for brevican, extremely low for hyaluronan and neurocan, and virtually no immunoreactivity was detectable for phosphacan. The granular configuration of perineuronal nets became more predominant with advancing age of the mutant animals, indicating the continued abnormal aggregation of chondroitin sulphate proteoglycans complexed with hyaluronan. As shown by electron microscopy in the cerebral cortex, the disruption of perineuronal nets was not accompanied by apparent changes in the synaptic structure on net-bearing neurons. The regional distribution patterns and the temporal course of development of perineuronal nets were not obviously changed in the mutant. We conclude that the lack of TN-R initially and continuously disturbs the molecular scaffolding of extracellular matrix components in perineuronal nets. This may interfere with the development of the specific micromilieu of the ensheathed neurons and adjacent glial cells and may also permanently change their functional properties. J. Comp. Neurol. 428:616–629, 2000. © 2000 Wiley-Liss, Inc.
A number of experiments have shown that neurotrophins are involved in the development and plasticity of the visual cortex (Bonhoeffer, T., Curr. Op. Neurobiol., 6, 119 1996). A possible mechanism underlying these effects is the neurotrophin modulation of synaptic transmission. We investigated whether nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) can modulate the release of neurotransmitter in the rat visual cortex at the peak of the critical period for plasticity (P23). The release of glutamate, acetylcholine and gamma-aminobutyric acid (GABA) from visual cortical synaptosomes was analysed in continuous perfusion conditions. We found that NGF enhances the depolarization-evoked release of glutamate (≈ 90%) and acetylcholine (≈ 35%) but not that of GABA. By contrast, BDNF enhances the depolarization-evoked release of all three neurotransmitters investigated (≈ 30%). BDNF and NGF were ineffective on basal release of neurotransmitters. The effect of NGF was not blocked by cholinergic antagonists atropine and mecamylamine. NGF and BDNF potentiation of transmitter release was strongly but not completely blocked by K252a, a tyrosine kinase inhibitor. The role of TrkA and p75NTR receptors was investigated in NGF-induced potentiation of glutamate release. Block of NGF binding to p75NTR using specific blocking antibodies (REX-IgG) slightly but significantly reduced the effect of NGF. Activation of TrkA in isolation by RTA-IgG, an antibody that specifically activates TrkA, was less effective than activation of both receptors by NGF. These results show that neurotrophin action on neurotransmitter release was mostly mediated by Trk receptors with p75NTR having a little but significant positive role. Antigen blot analysis showed the presence of TrkA, TrkB and p75NTR receptors in the visual cortex.
Numerous studies of the past decade have illuminated the importance of intercellular adhesion events for neural pattern formation. It has been documented that members of the Ig and cadherin gene superfamilies, that glycoproteins and, probably to some extent, proteoglycans of the extracellular matrix play a role in this context. Recent observations suggest that, in addition to adhesive interactions, repulsive and/or inhibitory phenoma are also of importance in regulating neural pattern formation. Several molecules are under study which are cosidered possible mediators of inhibitory interactions in the nervous system. The hypothesis has been advanced that some of these might be partially responsible for restrictive, boundary-like properties ascribed to glial cells in developing and regenerating tissues. The current review summarizes these studies and focusses on molecular aspects of boundary and compartmentation phenomena. © 1995 Wiley-Liss, Inc.
The mitogen-activated protein kinase ERK has recentlybecome a focus of studies of synaptic plasticity and learning and memory. Dueto the prominent role of potassium channels in regulating the electricalproperties of membranes, modulation of these channels by ERK could play animportant role in mediating learning-related synaptic plasticity in the CNS.Kv4.2 is a Shal-type potassium channel that passes an A-type current and islocalized to dendrites and cell bodies in the hippocampus. The sequence ofKv4.2 contains several consensus sites for ERK phosphorylation. In the presentstudies, we tested the hypothesis that Kv4.2 is an ERK substrate. Wedetermined that the Kv4.2 C-terminal cytoplasmic domain is an effective ERK2substrate, and that it is phosphorylated at three sites: Thr602,Thr607, and Ser616. We used this information to developantibodies that recognize Kv4.2 phosphorylated by ERK2. One of ourphospho-site-selective antibodies was generated using a triply phosphorylatedpeptide as the antigen. We determined that this antibody recognizesERK-phosphorylated Kv4.2 in COS-7 cells transfected with Kv4.2 and nativeERK-phosphorylated Kv4.2 in the rat hippocampus. These observations indicatethat Kv4.2 is a substrate for ERK in vitro and in vivo, and suggest that ERKmay regulate potassium-channel function by direct phosphorylation of thepore-forming α subunit.
Tissue-type plasminogen activator (tPA) plays important roles in the regulation of synaptic plasticity in the hippocampus and cerebellum. We found that the expression of tPA mRNA in the visual cortex was increased significantly by the peripheral administration of lthreo-3,4-dihydroxyphenylserine (l-threo-DOPS; 100 mg/kg, i.p.), which we had previously shown to have a promotive effect on ocular dominance (OD) plasticity. When plasminogen activator inhibitor-1 (PAI-1; 100 μM in an osmotic minipump) was infused into the kitten visual cortex, OD plasticity was suppressed; i.e. a significantly large number of binocular cells was recorded in the PAI-1-infused cortex following monocular deprivation. These results, therefore, suggest that the PA system is involved in the promotive effect of l-threo-DOPS in OD plasticity.
Activation of the transcription factor CREB is thought to be important in the formation of long-term memory in several animal species. The phosphorylation of a serine residue at position 133 of CREB is critical for activation of CREB. This phosphorylation is rapid when driven by brief synaptic activity in hippocampal neurons. It is initiated by a highly local, rise in calcium ion concentrations near the cell membrane, but culminates in the activation of a specific calmodulin-dependent kinase known as CaMK IV, which is constitutively present in the neuronal nucleus. It is unclear how the signal is conveyed from the synapse to the nucleus. We show here that brief bursts of activity cause a swift (approximately 1 min) translocation of calmodulin from the cytoplasm to the nucleus, and that this translocation is important for the rapid phosphorylation of CREB. Certain Ca2+ entry systems (L-type Ca2+ channels and NMDA receptors) are able to cause mobilization of calmodulin, whereas others (N- and P/Q-type Ca2+ channels) are not. This translocation of calmodulin provides a form of cellular communication that combines the specificity of local Ca2+ signalling with the ability to produce action at a distance.
N-methyl-d-aspartate receptors (NMDAR) mediate long-lasting changes in synapse strength via downstream signaling pathways. We report proteomic characterization with mass spectrometry and immunoblotting of NMDAR multiprotein complexes (NRC) isolated from mouse brain. The NRC comprised 77 proteins organized into receptor, adaptor, signaling, cytoskeletal and novel proteins, of which 30 are implicated from binding studies and another 19 participate in NMDAR signaling. NMDAR and metabotropic glutamate receptor subtypes were linked to cadherins and L1 cell-adhesion molecules in complexes lacking AMPA receptors. These neurotransmitter-adhesion receptor complexes were bound to kinases, phosphatases, GTPase-activating proteins and Ras with effectors including MAPK pathway components. Several proteins were encoded by activity-dependent genes. Genetic or pharmacological interference with 15 NRC proteins impairs learning and with 22 proteins alters synaptic plasticity in rodents. Mutations in three human genes (NF1, Rsk-2, L1) are associated with learning impairments, indicating the NRC also participates in human cognition.
In the mammalian central nervous system, receptors for excitatory amino acid neurotransmitters such as the alpha-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid (AMPA)-kainate receptor mediate a large fraction of excitatory transmission. Currents induced by activation
of the AMPA-kainate receptor were potentiated by agents that specifically stimulate adenosine 3',5'-monophosphate (cAMP)-dependent
protein kinase A (PKA) activity or were supported by intracellular application of the catalytic subunit of PKA by itself or
in combination with cAMP. Furthermore, depression of these currents by a competitive inhibitor of PKA indicates that AMPA-kainate
receptors are regulated by endogenous PKA. Endogenous protein phosphatases also regulate these receptors because an inhibitor
of cellular phosphates enhanced kainate currents. Modulation of PKA and phosphatases may regulate the function of these receptors
and thus contribute to synaptic plasticity in hippocampal neurons.
Receptor channels activated by glutamate, an excitatory neurotransmitter in the mammalian brain, are involved in processes
such as long-term potentiation and excitotoxicity. Studies of glutamate receptor channels expressed in cultured hippocampal
pyramidal neurons reveal that these channels are subject to neuromodulatory regulation through the adenylate cyclase cascade.
The whole-cell current response to glutamate and kainate [a non-NMDA (N-methyl-D-aspartate) receptor agonist] was enhanced
by forskolin, an activator of adenylate cyclase. Single-channel analysis revealed that an adenosine 3',5'-monophosphate-dependent
protein kinase (PKA) increases the opening frequency and the mean open time of the non-NMDA-type glutamate receptor channels.
Analysis of synaptic events indicated that forskolin, acting through PKA, increased the amplitude and decay time of spontaneous
excitatory postsynaptic currents.
Excerpt
The neurons in the mature mammalian central nervous system (CNS) are an enormously diverse group of cells. The acquisition of mature, differentiated neuronal properties takes place over an extended developmental period, through a number of different mechanisms. Some of the very last events in neuronal development occur late in the postnatal period, when the mature set of synapses between neurons and their targets is selected and the adult anatomical and physiological properties of neurons are acquired. Experiments in many different systems have shown that the mature set of synapses is selected from an initial set by selective stabilization of some synapses and elimination of others (for review, see Purves and Lichtman 1985). The process of synapse selection is governed, at least in part, by neuronal activity. Temporal matching of pre-and postsynaptic activity is thought to be critical in determining whether a synapse will be retained or lost. Environmental stimuli (such...
GABA, the major inhibitory neurotransmitter in the mammalian brain, binds to GABAA receptors, which form chloride ion channels. The predicted structure of the GABAA receptor places a consensus phosphorylation site for cAMP-dependent protein kinase (PKA) on an intracellular domain of the channel. Phosphorylation by various protein kinases has been shown to alter the activity of certain ligand- and voltage-gated ion channels. We have examined the role of phosphorylation by the catalytic subunit of PKA in the regulation of GABAA receptor channel function using whole-cell and excised outside-out patch-clamp techniques. Inclusion of the catalytic subunit of PKA in the recording pipettes significantly reduced GABA-evoked whole-cell and single-channel chloride currents. Both heat inactivation of PKA and addition of the specific protein kinase inhibitor peptide prevented the reduction of GABA-evoked currents by PKA. Neither mean channel open time nor channel conductance was affected by PKA. The reduction in GABA receptor current by PKA was primarily due to a reduction in channel opening frequency.
Monoclonal antibody Cat-301 was previously shown to recognize a surface-associated antigen on subsets of mammalian CNS neurons whose expression is regulated by neuronal activity early in an animal's postnatal life. We now present the partial purification and characterization of the Cat-301 antigen and demonstrate that it is a chondroitin sulfate proteoglycan. Extracellular localization of the Cat-301 epitope is demonstrated by staining live, intact neurons in situ. Extraction of the antigen from membranes in the absence of detergent indicates that it is either a peripheral membrane protein or a component of an extracellular matrix. The Cat-301 antigen migrates on Western blots of SDS gels with a molecular weight of integral of 680,000 dalton and is purified by DEAE chromatography and Sepharose gel filtration in 8 M urea (pH 4.9) buffer. The antigen is sensitive to chondroitinase ABC, indicating that it is a chondroitin sulfate proteoglycan. Furthermore, we provide strong evidence that the biochemically characterized antigen is indeed the histologically detected species by using a second antibody, Cat-304, that produces immunohistological staining patterns identical to those of Cat-301 and reacts with the purified antigen, but at a distinct epitope. Our earlier developmental findings and the present localization and biochemical results suggest that the antigen may play a role in the maturation of functional connections between neurons, perhaps through stabilization of axosomatic and axodendritic synapses.
Many hypotheses for the specificity of connections in the nervous system postulate the presence of surface chemical differences between neurons. Hybridoma technology offers a potential route to identify such surface antigenic differences between neurons. Monoclonal antibody Cat-301 was one of a panel of antibodies generated by immunizing mice with homogenized adult cat spinal cord. At the light microscopic level, Cat-301 recognizes a subset of neurons in many areas of the vertebrate central nervous system. This report shows at the ultrastructural level that Cat-301 binds to a surface antigen on neurons in the intact vertebrate central nervous system. Cat-301-positive neurons carry the antigen on cell bodies and proximal dendrites but not on axons. Using secondary antibody labeled with horseradish peroxidase, we show that antibody binding sites are present along the surfaces of neurons and extend around presynaptic profiles but are excluded from the synaptic cleft. The distribution of the Cat-301 antigen at central synapses is similar to that described for some components of the extracellular matrix of the neuromuscular junction. This study demonstrates that a specific surface antigen is found on a subset of neurons and suggests that other surface markers may be present on other subsets of mammalian central nervous system neurons. Antibodies against this antigen and other surface antigens may allow insight into the mechanisms involved in the formation and maintenance of synaptic connections in the central nervous system.
Altering the balance of activity between the two eyes during the critical period for visual-system development profoundly affects competitive interactions among neurons in the lateral geniculate nucleus and primary visual cortex. Neurons in the lateral geniculate nucleus that are deprived of activity by closing or silencing one eye atrophy as a result of competition with non-deprived neurons for some critical factor(s) presumed to be present in the cortex. Based on their actions in the developing visual system, neurotrophins are attractive candidates for such factors. We tested whether neurotrophins mediate intracortical competition of afferents from the lateral geniculate nucleus by using monocular deprivation and a new method for highly localized, in vivo delivery of neurotrophins. This method allowed unambiguous identification of neurons that were exposed to neurotrophin. Here we report that only one neurotrophin, the TrkB ligand NT-4, rescued neurons in the lateral geniculate nucleus from the dystrophic effects of monocular deprivation.
A mechanism by which the nerve growth factor (NGF) signal is transduced to the nucleus to induce gene expression has been characterized. An NGF-inducible, Ras-dependent protein kinase has been identified that catalyzes the phosphorylation of the cyclic AMP response element-binding protein (CREB) at Ser-133. Phosphorylation of Ser-133 stimulates the ability of CREB to activate transcription in NGF-treated cells. These findings suggest that CREB has a more widespread function than previously believed and functions in the nucleus as a general mediator of growth factor responses.
The requirement of protein and messenger RNA synthesis for long-term memory suggests that neural activity induced by learning initiates a cascade of gene expression. Here we use differential screening to identify five immediate-early genes induced by neuronal activity. One of these is tissue-plasminogen activator (tPA), an extracellular serine protease, which is induced with different spatial patterns in the brain by three activity-dependent events: (1) convulsive seizure increases expression of tPA in the whole brain; (2) stimulation of the perforant path produces an epileptiform after-discharge that ultimately leads to kindling increases the levels of tPA throughout the hippocampus bilaterally; and (3) brief high-frequency stimulation of the perforant path that produces long-term potentiation (LTP) causes an NMDA (N-methyl-D-aspartate) receptor-mediated increase in the levels of tPA mRNA which is restricted to the granule cells of the ipsilateral dentate gyrus. As release of tPA is correlated with morphological differentiation, the increased expression of tPA may play a role in the structural changes that accompany activity-dependent plasticity.
Gene expression regulated by the cAMP response element (CRE) has been implicated in synaptic plasticity and long-term memory. It has been proposed that CRE-mediated gene expression is stimulated by signals that induce long-term potentiation (LTP). To test this hypothesis, we made mice transgenic for a CRE-regulated reporter construct. We focused on long-lasting long-term potentiation (L-LTP), because it depends on cAMP-dependent protein kinase activity (PKA) and de novo gene expression. CRE-mediated gene expression was markedly increased after L-LTP, but not after decremental UP (D-LTP). Furthermore, inhibitors of PKA blocked L-LTP and associated increases in CRE-mediated gene expression. These data demonstrate that the signaling required for the generation of L-LTP but not D-LTP is sufficient to stimulate CRE-mediated transcription in the hippocampus.
The extracellular matrix is involved in various morphogenetic processes which are accompanied by changes in its physicochemical properties and spatial organization. In the adult brain it contributes to cellular communication and the regulation of neuronal activity. The present study deals with the postnatal appearance and transformation into adult distribution patterns of extracellular matrix components related to chondroitin-sulphate proteoglycans (CSPGs) in the rat brain. The differential accumulation of these components in neuropil and in perineuronal nets (PNs) enriched in certain regions was examined in 0-, 7-, 14-, 21- and 35-day-old rats and adult animals using the N-acetylgalactosamine-binding Wisteria floribunda agglutinin (WFA) and immunocytochemical detection of CSPGs. The lectin stained the olfactory-bulb glomerular layer and layer Ia of piriform and entorhinal cortex already in newborn animals. On postnatal day 7 diffuse neuropil staining was additionally found in certain subcortical nuclei and in deep neocortical layers. The first sharply contoured PNs were detected at this age in the brain stem, indicating the more advanced maturation of matrix components in subcortical regions. CSPG immunoreactivity yielded staining patterns largely identical to WFA-binding patterns but appeared only between postnatal day 14 and 21. The adult-like stage was revealed with both methods between 21 and 35 days after birth. The results provide further evidence that the accumulation of certain CSPGs in the extracellular space is spatiotemporally related to distinct patterns of neuronal activity at the regional and cellular level.
The expression of immediate-early genes that code for transcription factors has been extensively studied in the brain with regard to imaging functional activity. The components of the AP-1 transcription factor--in particular, c-Fos--and Zif268 have been widely used for this purpose. However, the precise details by which they are induced after synaptic stimulation remain unknown. Furthermore, the roles of these two proteins in neurons remains speculative and include such varied functions as short-term maintenance of cellular homeostasis to long-term changes that guide cortical plasticity. Current efforts at elucidating the physiological roles of AP-1 and Zif268 rely on assessing their expression in response to different conditions of sensory and pharmacological stimulation. In this review, we have examined the expression patterns of these transcription factors in the mammalian visual cortex under different conditions, with particular emphasis on the constitutive levels and how they change after visual deprivation and stimulation. A synthesis of this information offers further insight into their likely functions and the extent to which transcription factors may represent patterns of neural activity as a possible prelude to plastic events.
Long-term potentiation (LTP), a cellular model of learning and memory, requires calcium-dependent protein kinases. Induction of LTP increased the phosphorus-32 labeling of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPA-Rs), which mediate rapid excitatory synaptic transmission. This AMPA-R phosphorylation appeared to be catalyzed by Ca2+- and calmodulin-dependent protein kinase II (CaM-KII): (i) it correlated with the activation and autophosphorylation of CaM-KII, (ii) it was blocked by the CaM-KII inhibitor KN-62, and (iii) its phosphorus-32 peptide map was the same as that of GluR1 coexpressed with activated CaM-KII in HEK-293 cells. This covalent modulation of AMPA-Rs in LTP provides a postsynaptic molecular mechanism for synaptic plasticity.
We have examined the hypothesis that the segregation of LGN axon terminals into ocular dominance (OD) patches in layer 4 of the visual cortex requires neurotrophins, acting as signals to modulate the pattern of synaptic connectivity. Neurotrophin receptor antagonists, composed of the extracellular domain of each member of the trk family of neurotrophin receptors fused to a human Fc domain, were infused directly into visual cortex during the peak phase of OD column formation. Infusion of trkB-IgG, which binds BDNF and NT-4/5, inhibited the formation of OD patches within layer 4, while trkA-IgG and trkC-IgG, which preferentially bind NGF and NT-3, respectively, had no effect. The autoradiographic labeling of LGN terminals in cortical layer 4 was reduced by trkB-IgG, in contrast with the increased labeling observed following NT-4/5 infusion. These data suggest that an endogenous ligand of trkB, normally present in limiting amounts within visual cortex, is necessary for the selective growth and remodeling of LGN axons into eye-specific patches.
Activity-dependent alteration in synaptic strength is a fundamental property of the vertebrate central nervous system and is thought to underlie learning and memory. The most extensively studied model of activity-dependent synaptic plasticity is long-term potentiation (LTP) of glutamate-responsive (glutamatergic) synapses, a widespread phenomenon involving multiple mechanisms. The best characterized form of LTP occurs in the CA1 region of the hippocampus, in which LTP is initiated by transient activation of NMDA (N-methyl-D-aspartate) receptors and is expressed as a persistent increase in synaptic transmission through AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate) receptors. This increase is due, at least in part, to a postsynaptic modification of AMPA-receptor function; this modification could be caused by an increase in the number of receptors, their open probability, their kinetics or their single-channel conductance. Here we show that the induction of LTP in the CA1 region of the hippocampus is often associated with an increase in single-channel conductance of AMPA receptors. This shows that elementary channel properties can be rapidly modified by synaptic activity and provides an insight into one molecular mechanism by which glutamatergic synapses can alter their strength.
Amblyopia is a developmental disorder of pattern vision. After surgical creation of esotropic strabismus in the first weeks of life or after wearing -10 diopter contact lenses in one eye to simulate anisometropia during the first months of life, macaques often develop amblyopia. We studied the response properties of visual cortex neurons in six amblyopic macaques; three monkeys were anisometropic, and three were strabismic. In all monkeys, cortical binocularity was reduced. In anisometropes, the amblyopic eye influenced a relatively small proportion of cortical neurons; in strabismics, the influence of the two eyes was more nearly equal. The severity of amblyopia was related to the relative strength of the input of the amblyopic eye to the cortex only for the more seriously affected amblyopes. Measurements of the spatial frequency tuning and contrast sensitivity of cortical neurons showed few differences between the eyes for the three less severe amblyopes (two strabismic and one anisometropic). In the three more severely affected animals (one strabismic and two anisometropic), the optimal spatial frequency and spatial resolution of cortical neurons driven by the amblyopic eye were substantially and significantly lower than for neurons driven by the nonamblyopic eye. There were no reliable differences in neuronal contrast sensitivity between the eyes. A sample of neurons recorded from cortex representing the peripheral visual field showed no interocular differences, suggesting that the effects of amblyopia were more pronounced in portions of the cortex subserving foveal vision. Qualitatively, abnormalities in both the eye dominance and spatial properties of visual cortex neurons were related on a case-by-case basis to the depth of amblyopia. Quantitative analysis suggests, however, that these abnormalities alone do not explain the full range of visual deficits in amblyopia. Studies of extrastriate cortical areas may uncover further abnormalities that explain these deficits.
Neurotrophins are a family of soluble ligands that promote the survival and differentiation of peripheral and central neurons and regulate synaptic function. The two neurotrophins, brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT4), bind and activate a single high-affinity receptor, TrkB. Experiments in cell culture have revealed that an intact Shc adaptor binding site on TrkB and subsequent activation of the Ras/MAPK pathway are important for neuronal survival and neurite outgrowth. To elucidate the intracellular signaling pathways that mediate the diverse effects of BDNF and NT4 in vivo, we have mutated in the mouse germline the Shc binding site in the trkB gene. This trkB(shc) mutation revealed distinctive responses to BDNF and NT4. While nearly all NT4-dependent sensory neurons were lost in trkB(shc/shc) mutant mice, BDNF-dependent neurons were only modestly affected. Activation of MAP kinases and in vitro survival of cultured trkB(shc/shc) neurons were reduced in response to both neurotrophins, with NT4 being less potent than BDNF, suggesting differential activation of TrkB by the two ligands. Moreover, while the Ras/MAPK pathway is required for in vitro differentiation of neuronal cells, trkB(shc/shc) mutant mice do not show any defects in BDNF-dependent differentiation of CNS neurons or in the function of sensory neurons that mediate innocuous touch.
Pioneering work has shown that pharmacological blockade of the N-methyl-D-aspartate (NMDA) receptor channel reduces ocular dominance plasticity. However, the results also show that doses of NMDA receptor antagonists that have an effect on ocular dominance plasticity profoundly reduce sensory responses and disrupt stimulus selectivity of cortical cells. It is, therefore, not possible to determine whether effects of NMDA receptor blockade on visual plasticity result from a specific role of NMDA receptors or from the reduction in sensory response. We have used an alternate approach to examine this question. We performed knockdown experiments using antisense oligodeoxynucleotides (ODNs) complementary to mRNA coding the NR1 subunit of the NMDA receptor. After 5 days of antisense, but not sense, ODN treatment NMDA receptor-mediated synaptic transmission was reduced markedly relative to the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor response, as indicated by whole cell patch-clamp recordings in the cortical slice preparation. This suppression of NMDA receptor-mediated currents was due to a selective reduction in the NR1 protein near the injection site relative to the untreated hemisphere in the same animal, as indicated by immunocytochemistry and Western blotting. In contrast, AMPA receptors were not affected by the antisense ODN treatment indicating specificity of effects. Another major effect of this treatment was to decrease ocular dominance plasticity. Ferrets that were monocularly deprived 1 wk during the antisense ODN treatment had ocular dominance histograms similar to those found in untreated, nondeprived animals. In contrast, ferrets treated with sense ODN and monocularly deprived had ocular dominance histograms resembling those of untreated, monocularly deprived animals. The effects on ocular dominance plasticity did not result from a disruption of sensory responses because maximum responses as well as orientation and direction selectivity of cortical cells were not affected by the treatment. In conclusion, the present results show that antisense techniques can accomplish more selective manipulations of cortical function than is possible with traditional pharmacological agents. Use of this approach also provides unambiguous evidence for a specific role of NMDA receptors in visual plasticity.
A number of experiments have shown that neurotrophins are involved in the development and plasticity of the visual cortex (Bonhoeffer, T., Curr. Op. Neurobiol., 6, 119, 1996). A possible mechanism underlying these effects is the neurotrophin modulation of synaptic transmission. We investigated whether nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) can modulate the release of neurotransmitter in the rat visual cortex at the peak of the critical period for plasticity (P23). The release of glutamate, acetylcholine and gamma-aminobutyric acid (GABA) from visual cortical synaptosomes was analysed in continuous perfusion conditions. We found that NGF enhances the depolarization-evoked release of glutamate (approximately 90%) and acetylcholine (approximately 35%) but not that of GABA. By contrast, BDNF enhances the depolarization-evoked release of all three neurotransmitters investigated (approximately 30%). BDNF and NGF were ineffective on basal release of neurotransmitters. The effect of NGF was not blocked by cholinergic antagonists atropine and mecamylamine. NGF and BDNF potentiation of transmitter release was strongly but not completely blocked by K252a, a tyrosine kinase inhibitor. The role of TrkA and p75NTR receptors was investigated in NGF-induced potentiation of glutamate release. Block of NGF binding to p75NTR using specific blocking antibodies (REX-IgG) slightly but significantly reduced the effect of NGF. Activation of TrkA in isolation by RTA-IgG, an antibody that specifically activates TrkA, was less effective than activation of both receptors by NGF. These results show that neurotrophin action on neurotransmitter release was mostly mediated by Trk receptors with p75NTR having a little but significant positive role. Antigen blot analysis showed the presence of TrkA, TrkB and p75NTR receptors in the visual cortex.
Although Ca2+-stimulated cAMP response element binding protein- (CREB-) dependent transcription has been implicated in growth, differentiation, and neuroplasticity, mechanisms for Ca2+-activated transcription have not been defined. Here, we report that extracellular signal-related protein kinase (ERK) signaling is obligatory for Ca2+-stimulated transcription in PC12 cells and hippocampal neurons. The sequential activation of ERK and Rsk2 by Ca2+ leads to the phosphorylation and transactivation of CREB. Interestingly, the Ca2+-induced nuclear translocation of ERK and Rsk2 to the nucleus requires protein kinase A (PKA) activation. This may explain why PKA activity is required for Ca2+-stimulated CREB-dependent transcription. Furthermore, the full expression of the late phase of long-term potentiation (L-LTP) and L-LTP-associated CRE-mediated transcription requires ERK activation, suggesting that the activation of CREB by ERK plays a critical role in the formation of long lasting neuronal plasticity.
Golgi ranked the peripheral reticulum--which adheres intimately to nerve cell surfaces--alongside the intracellular reticulum, or Golgi apparatus,which immortalized his name. At first dismissed as an artefact of capricious staining techniques, this peripheral reticulum, or perineuronal net, is now recognized as a genuine entity in neurocytology. It represents a complex of extracellular matrix molecules interposed between the meshwork of glial processes, from which they are indistinguishable, and nerve-cell surfaces. In no other branch of neuroscience has the waxing and waning of interest in any morphological entity been so pronounced as in the case of the perineuronal net. This review traces the history of this enigmatic structure from its conception to the present time, brings to light the keen observational powers of morphologists at the turn of the century and reveals how their sagacious forethought anticipated current thinking on the role of perineuronal nets.
Many distinct signaling pathways allow the cell to receive, process, and respond to information. Often, components of different
pathways interact, resulting in signaling networks. Biochemical signaling networks were constructed with experimentally obtained
constants and analyzed by computational methods to understand their role in complex biological processes. These networks exhibit
emergent properties such as integration of signals across multiple time scales, generation of distinct outputs depending on
input strength and duration, and self-sustaining feedback loops. Feedback can result in bistable behavior with discrete steady-state
activities, well-defined input thresholds for transition between states and prolonged signal output, and signal modulation
in response to transient stimuli. These properties of signaling networks raise the possibility that information for “learned
behavior” of biological systems may be stored within intracellular biochemical reactions that comprise signaling pathways.