Activation of Somatostatin Interneurons by Nicotinic Modulator Lypd6 Enhances Plasticity and Functional Recovery in the Adult Mouse Visual Cortex.

The limitation of plasticity in the adult brain impedes functional recovery later in life from brain injury or disease. This pressing clinical issue may be resolved by enhancing plasticity in the adult brain. One strategy for triggering robust plasticity in adulthood is to reproduce one of the hallmark physiological events of experience-dependent plasticity observed during the juvenile critical period: to rapidly reduce the activity of parvalbumin (PV)-expressing interneurons and disinhibit local excitatory neurons. This may be achieved through the enhancement of local inhibitory inputs, particularly those of somatostatin (SST)-expressing interneurons. However, to date the means for manipulating SST interneurons for enhancing cortical plasticity in the adult brain are not known. We show that SST interneuron-selective overexpression of Lypd6, an endogenous nicotinic signaling modulator, enhances ocular dominance plasticity in the adult primary visual cortex (V1). Lypd6 overexpression mediates a rapid experience-dependent increase in the visually evoked activity of SST interneurons as well as a simultaneous reduction in PV interneuron activity and disinhibition of excitatory neurons. Recapitulating this transient activation of SST interneurons using chemogenetics similarly enhanced V1 plasticity. Notably, we show that SST-selective Lypd6 overexpression restores visual acuity in amblyopic mice that underwent early long-term monocular deprivation. Our data in both male and female mice reveal selective modulation of SST interneurons and a putative downstream circuit mechanism as an effective method for enhancing experience-dependent cortical plasticity as well as functional recovery in adulthood.SIGNIFICANCE STATEMENT The decline of cortical plasticity after closure of juvenile critical period consolidates neural circuits and behavior, but this limits functional recovery from brain diseases and dysfunctions in later life. Here we show that activation of cortical somatostatin (SST) interneurons by Lypd6, an endogenous modulator of nicotinic acetylcholine receptors, enhances experience-dependent plasticity and recovery from amblyopia in adulthood. This manipulation triggers rapid reduction of PV interneuron activity and disinhibition of excitatory neurons, which are known hallmarks of cortical plasticity during juvenile critical periods. Our study demonstrates modulation of SST interneurons by Lypd6 to achieve robust levels of cortical plasticity in the adult brain and may provide promising targets for restoring brain function in the event of brain trauma or disease.

The synaptic proteome during development and plasticity of the mouse visual cortex.

During brain development, the neocortex shows periods of enhanced plasticity, which enables the acquisition of knowledge and skills that we use and build on in adult life. Key to persistent modifications of neuronal connectivity and plasticity of the neocortex are molecular changes occurring at the synapse. Here we used isobaric tag for relative and absolute quantification to measure levels of 467 synaptic proteins in a well-established model of plasticity in the mouse visual cortex and the regulation of its critical period. We found that inducing visual cortex plasticity by monocular deprivation during the critical period increased levels of kinases and proteins regulating the actin-cytoskeleton and endocytosis. Upon closure of the critical period with age, proteins associated with transmitter vesicle release and the tubulin- and septin-cytoskeletons increased, whereas actin-regulators decreased in line with augmented synapse stability and efficacy. Maintaining the visual cortex in a plastic state by dark rearing mice into adulthood only partially prevented these changes and increased levels of G-proteins and protein kinase A subunits. This suggests that in contrast to the general belief, dark rearing does not simply delay cortical development but may activate signaling pathways that specifically maintain or increase the plasticity potential of the visual cortex. Altogether, this study identified many novel candidate plasticity proteins and signaling pathways that mediate synaptic plasticity during critical developmental periods or restrict it in adulthood.

O impacto da visão monocular congênita versus adquirida na qualidade de visão autorrelatada / Impact of congenital versus acquired monocular vision as self-reported vision

Objetivos: Quando a visão de um olho está preservada (visão monocular) e há alto risco, baixo prognóstico e/ou recursos limitados para a cirurgia do olho contralateral, não é claro se o beneficio da binocularidade supera o da reorientação para visão monocular. O objetivo é quantificar o impacto da qualidade de visão referida entre a condição binocular e monocular e, nesse último caso, entre congênita e adquirida. Métodos: Pacientes com acuidade visual (AV) com AV>0,5 em cada olho foram submetidos ao questionário estruturado de 14 perguntas (VF-14), onde a pontuação de 0 a 100 indica o nível de satisfação do paciente com sua visão, variando de baixo a alto respectivamente. Dados epidemiológicos e pontuações dos quatro grupos foram registrados e submetidos à análise estatística. Resultados: A entrevista pelo VF-14 com 56 indivíduos revelou que a pontuação mais alta foi similar entre os controles e os portadores de visão monocular congênita, e níveis intermediários e baixos foram obtidos por indivíduos com visão monocular adquirida e cegos bilaterais, respectivamente (p<0,001). As atividades mais difíceis para os indivíduos com visão monocular adquirida foram identificar letras pequenas, reconhecer pessoas, distinguir sinais de trânsito e assistir TV. Conclusão: O estudo confirmou que a perda da visão tem impacto desfavorável no desempenho referido das atividades sendo maior na visão monocular adquirida do que na congênita. Os dados sugerem que medidas de reabilitação devem ser consideradas para melhorar a qualidade da visão em doenças intratáveis ou de alto risco ou de baixo prognóstico.

Purpose: When the vision in one eye is preserved (monocular vision) and there is high risk, low prognosis and/or limited resources to the fellow eye surgery, it is unclear if the benefit of binocularity outweighs the reorientation for monocular vision. The goal is to quantify the impact of the quality of vision of both binocular and monocular condition, and in this latter case, between congenital and acquired. Methods: Patients with visual acuity (VA)>0.5 in each eye underwent a structured questionnaire of 14 questions (VF-14), which the score 0-100 indicates the level of patient satisfaction with their vision, ranging from low to high respectively. Epidemiological data and scores of the four groups were recorded and analyzed statistically. Results: The interview by the VF-14 with 56 subjects revealed that the highest score was similar between controls and patients with congenital monocular vision, and low and intermediate levels were obtained by individuals with acquired monocular vision and bilaterally blind, respectively (p<0.001). The more difficult activities for individuals with acquired monocular vision were to identify small print, recognize people, to distinguish traffic lights and watch TV. Conclusion: The study confirmed that the vision loss has an adverse impact on the performance of such activities being higher in congenital than in acquired monocular vision. The data suggest that rehabilitation measures should be considered to improve the quality of vision in intractable diseases, high risk or low prognosis.

[Impact of congenital versus acquired monocular vision as self-reported vision]. / O impacto da visão monocular congênita versus adquirida na qualidade de visão autorrelatada.

PURPOSE: When the vision in one eye is preserved (monocular vision) and there is high risk, low prognosis and/or limited resources to the fellow eye surgery, it is unclear if the benefit of binocularity outweighs the reorientation for monocular vision. The goal is to quantify the impact of the quality of vision of both binocular and monocular condition, and in this latter case, between congenital and acquired. METHODS: Patients with visual acuity (VA)>0.5 in each eye underwent a structured questionnaire of 14 questions (VF-14), which the score 0-100 indicates the level of patient satisfaction with their vision, ranging from low to high respectively. Epidemiological data and scores of the four groups were recorded and analyzed statistically. RESULTS: The interview by the VF-14 with 56 subjects revealed that the highest score was similar between controls and patients with congenital monocular vision, and low and intermediate levels were obtained by individuals with acquired monocular vision and bilaterally blind, respectively (p<0.001). The more difficult activities for individuals with acquired monocular vision were to identify small print, recognize people, to distinguish traffic lights and watch TV. CONCLUSION: The study confirmed that the vision loss has an adverse impact on the performance of such activities being higher in congenital than in acquired monocular vision. The data suggest that rehabilitation measures should be considered to improve the quality of vision in intractable diseases, high risk or low prognosis.

Expression of immediate-early genes reveals functional compartments within ocular dominance columns after brief monocular inactivation.

Visual inputs from the 2 eyes in most primates activate alternating bands of cortex in layer 4C of primary visual cortex, thereby forming the well-studied ocular dominance columns (ODCs). In addition, the enzymatic reactivity of cytochrome oxidase (CO) reveals "blob" structures within the supragranular layers of ODCs. Here, we present evidence for compartments within ODCs that have not been clearly defined previously. These compartments are revealed by the activity-dependent mRNA expression of immediate-early genes (IEGs), zif268 and c-fos, after brief periods of monocular inactivation (MI). After a 1-3-h period of MI produced by an injection of tetrodotoxin, IEGs were expressed in a patchy pattern that included infragranular layers, as well as supragranular layers, where they corresponded to the CO blobs. In addition, the expressions of IEGs in layer 4C were especially high in narrow zones along boundaries of ODCs, referred to here as the "border strips" of the ODCs. After longer periods of MI (>5 h), the border strips were no longer apparent. When either eyelid was sutured, changes in IEG expression were not evident in layer 4C; however, the patchy pattern of the expression in the infragranular and supragranular layers remained. These changes of IEG expression after MI indicate that cortical circuits involving the CO blobs of the supragranular layers include aligned groups of neurons in the infragranular layers and that the border strip neurons of layer 4C are highly active for a 3-h period after MI.

Monocular visual deprivation in macaque monkeys: a profile in the gene expression of lateral geniculate nucleus by laser capture microdissection.

PURPOSE: Amblyopia is the most common cause of visual impairment in children. Early detection of amblyopia and subsequent intervention are vital in preventing visual loss. Understanding the molecular pathogenesis of amblyopia would greatly facilitate development of therapeutic interventions. An animal model of amblyopia induced by monocular vision deprivation has been extensively studied in terms of anatomic and physiologic alterations that affect visual pathways. However, the molecular events underlying these changes are poorly understood. This study aimed to characterize changes of gene expression profiles in the lateral geniculate nucleus (LGN) associated with amblyopia induced by monocular visual deprivation. METHODS: Monocular vision deprivation was generated by either opaque dark contact lens or tarsorrhaphy of newborn rhesus monkeys. LGN was harvested at two or four months following induction of vision deprivation. Laser capture microdissection was used to obtain individual LGN layers for total RNA isolation. Linear T7-based in vitro RNA amplification was used to obtain sufficient RNA to conduct DNA microarray studies. The resulting Affymetrix GeneChip Expression data were analyzed using Affymetrix GeneChip Operating Software. Real-time quantitative polymerase chain reaction and in situ hybridization were used to further analyze expression of selected genes. RESULTS: Using 52,699 microarray probe sets from a Rhesus array, we identified 116 transcripts differentially expressed between deprived and nondeprived parvocellular layers: 45 genes were downregulated and 71 genes were upregulated in deprived parvocellular layers. We also observed substantial changes in deprived magnocellular laminae: 74 transcripts exhibited altered expression, 42 genes were downregulated, and 32 genes were upregulated. The genes identified in this study are involved in many diverse processes, including binding (calcium ion binding, nucleic acid binding, and nucleotide binding), catalytic activity, and signal transducer activity. CONCLUSIONS: There were significant differences in gene expression profiles between deprived and nondeprived parvocellular layers and magnocellular laminae of LGN. These alterations in gene expression may play a critical role in the molecular pathogenesis of amblyopia. The genes identified in this study may provide potential targets for therapeutic intervention of this disease.

Reversible blockade of experience-dependent plasticity by calcineurin in mouse visual cortex.

Numerous protein kinases have been implicated in visual cortex plasticity, but the role of serine/threonine protein phosphatases has not yet been established. Calcineurin, the only known Ca2+/calmodulin-activated protein phosphatase in the brain, has been identified as a molecular constraint on synaptic plasticity in the hippocampus and on memory. Using transgenic mice overexpressing calcineurin inducibly in forebrain neurons, we now provide evidence that calcineurin is also involved in ocular dominance plasticity. A transient increase in calcineurin activity is found to prevent the shift of responsiveness in the visual cortex following monocular deprivation, and this effect is reversible. These results imply that the balance between protein kinases and phosphatases is critical for visual cortex plasticity.

Effects of monocular enucleation on parvalbumin in rat visual system during postnatal development.

PURPOSE: To evaluate the hypothesis that the expression of the calcium-binding protein parvalbumin (PV) in a subpopulation of gamma-aminobutyric acid (GABA)ergic neurons is an appropriate molecular marker for the effect on ocular dominance plasticity of monocular deprivation during the postnatal sensitive period. METHODS: Long-Evans rats underwent monocular enucleation immediately before eye opening (postnatal day [P] 14). Immunohistochemical analysis using anti-PV antibody was performed on the superior colliculus (SC) and lateral geniculate nucleus (LGN) at P45. In the visual cortex (VC) developmental changes in immunoreactivity were also examined at the ages of P17, P20, P27, and P45. Northern blot analysis for PV mRNA was also performed at P45. Changes in PV expression in the visual system of these rats were evaluated by use of a computer-based quantitative technique. RESULTS: PV-immunoreactive neurons were present in the SC and VC, whereas only a few were found in the LGN. The monocular enucleation at the onset of the sensitive period markedly reduced PV immunoreactivity in the neuropil of the SC, contralateral to the enucleated eye when examined one month later. No consistent and significant change in PV immunoreactivity was found in either the LGN or the VC. The number of PV-immunoreactive neurons in the VC rapidly decreased to the adult level during the middle of the sensitive period. The expression of PV mRNA in these central visual structures was not affected by early monocular enucleation. CONCLUSIONS: Expression of PV is developmentally regulated, and marked changes in its protein expression in the SC can be induced by monocular enucleation. Contrary to the original hypothesis, monocular enucleation did not consistently affect the expression of PV in the rat VC. The expression of PV is probably regulated by multiple factors, not merely by binocular competition.

Differential regulation of brain-derived neurotrophic factor messenger RNA cellular expression in the adult rat visual cortex.

In this study, we report a comparative analysis of the distribution of brain-derived neurotrophic factor messenger RNA in the binocular primary visual cortex of rats analysed at the end of the critical period for monocular deprivation (postnatal day 35) and during adulthood (postnatal day 90). High-resolution non-isotopic in situ hybridization coupled with Nissl staining allowed to determine the relative number of neurons expressing brain-derived neurotrophic factor messenger RNA. In postnatal day 90 rats, the relative number of neurons positive for brain-derived neurotrophic factor messenger RNA significantly decreases in layer II/III with respect to postnatal day 35 animals, being constant in all the other cortical layers. Moreover, we demonstrate that dark rearing for 22 days, starting from postnatal day 90, determines: (i) a decrease of the overall level of brain-derived neurotrophic factor messenger RNA with a consequent reduction of labelling intensity in all cells throughout cortical layers II-VI; (ii) an increase of cell numbers expressing brain-derived neurotrophic factor messenger RNA in layers IV and V; and (iii) a decreased intensity of staining for brain-derived neurotrophic factor messenger RNA in dendrites after dark rearing. A re-exposure to light for 2 h after the period of darkness almost restores the number of brain-derived neurotrophic factor RNA-positive neurons. We conclude that the maturation of brain-derived neurotrophic factor messenger RNA in neurons of layer II/III goes beyond postnatal days 35-40, which can be considered the end of the critical period [Fagiolini M. et al. (1994) Vis. Res., 34, 709-720]. Moreover, we show that the cellular expression of brain-derived neurotrophic factor messenger RNA is regulated by light in adult rats as well as during development.