The main goal of our work is focused on understanding neuropsychiatric disorders while dissecting the neuronal circuits controlling behaviors. We study synaptic and postsynaptic density proteins implicated in autism and schizophrenia in specific cell-types and neuronal circuits. We want to understand how synaptic computations give rise to social behavioral programs and to uncover the genetic elements that regulate sociability. To achieve our goals, we use a combination of molecular genetics, optogenetics and electrophysiological approaches. We also apply our expertise in the development on novel, genetically engineered mouse models to create tools usable by the neuroscience community.


 

Current projects in the lab include:

Environmental and Epigenetic Alterations Affecting Social behaviors

Social interactions are complex behaviors displayed by most animal species. Overt dysfunction in sociability is a hallmark of neuropsychiatric disorders such as autism and schizophrenia, but abnormal social interaction in otherwise healthy individuals is itself a trigger for mental health disorders. For instance, several forms of social stress are well described to contribute to the onset of posttraumatic stress disorder and major depression. Early deprivation of maternal care is another form of social stress and is acknowledged to have a long-term effect on animal behavior and is one of the most potent, naturally occurring stressors.  Early life deprivation and adversity (EDA) are forms of stress that trigger alterations in gene expression through epigenetic mechanisms and that increase the risk for psychiatric disorders in adulthood. Chronic stress mediates structural modification in neuronal circuit function, leading to perturbed behavioral strategies. Nevertheless, the modifications occurring as a consequence of EDA, and the interplay between epigenetic mechanisms and circuit dysfunctions are not yet completely understood.

mGluR Signaling in Autism Spectrum Disorders

Autism spectrum disorders (ASDs) are early onset neurodevelopmental conditions characterized by persistent problems in social interaction and communication, as well as by the presence of stereotypies, restricted interests and repetitive behaviors. Genetic and genomic studies have identified a wide range of candidate genes scattered across the genome that display significant alterations ranging from single nucleotide rare variants to large chromosomal abnormalities. A key molecular focal point are the metabotropic glutamate receptors (mGluRs). Nevertheless, despite their clear involvement in autism pathology, the underlying molecular and cellular pathways regulating these receptors under disease conditions are poorly understood. Therefore, we are currently studying autism candidate genes that intersect with the regulation of mGluRs and that may spur a new understanding of the pathophysiological mechanism underlying forms of ASDs where there is mGluR dysfunction.

(Opto)Genetic  Engineering and Tool Development

We have wide range expertise in mouse molecular genetics, having developed several animal models and transgenic tools. Some of our present interests are in the field of Optogenetics. Channelrhodopsin-2 (ChR2) is a key component in optogenetic applications absorbing blue light to cause a switch in the all-trans-retinal chromophore, and a subsequent conformational change in the protein. During long term transgenic expression, the channel does not require exogenous co-factors and retains its ability to induce neuronal firing with millisecond precision. The rapid opening and closure of the channel, the presence of retinal in most vertebrate cells, and the fact that ChR2 can be genetically encoded are attractive features that make ChR2 a useful tool for therapeutic applications. However, most optogenetic tools are excited only by blue light, and the few exceptions display problematic sustained depolarization between light pulses and generally display inadequate currents. To overcome these limitations, we are investigating and developing novel ChR2 mutants.

Funding
 

Designação do projeto:  WINorLOSE .: Hierarquia social e adversidades no período juvenil: regulação neuroepigenética e modulação optogenética dos circuitos do córtex pré-frontal

Código do projeto: POCI-01-0145-FEDER-016682

Região de intervenção: Centro - Coimbra Entidade Beneficiária:  CNC - Centro de Neurociências e Biologia Celular

Custo total elegível: 198.205,00€

Apoio financeiro da União Europeia: FEDER – 151.930,70€

Apoio financeiro público nacional/regional: FCT – 46.274,30 €

Objetivo Principal:
Adversidades e privações sofridas durante a infância (API) são tipos de stress que podem desencadear alterações na expressão génica através de mecanismos epigenéticos e que podem levar ao aumento do risco de doenças psiquiátricas. O stress crónico promove modificações estruturais nos circuitos neuronais e leva a uma perturbação na escolha de estratégias comportamentais. Contudo, as modificações epigenéticas, os genes e os circuitos envolvidos nas API não são conhecidas.

Ao abrigo do projecto WINorLose caracterizámos um processo de disfunção nos comportamentos sociais de animais modelo de API e num modelo de disfunção genética. As principais perguntas a responder ao abrigo deste projecto foram:

1)    Existem determinantes moleculares que preveem ou influenciam o comportamento dominante ou submisso?

2)    Quais os mecanismos envolvidos nos processos de controlo social, de hierarquia social e onde é que essa informação é codificada no cérebro?

Abordamos estes objectivos em duas linhas temáticas:
(i)    Um modelo de API em murganhos, usando um protocolo de separação maternal e stress materno

(ii)    Usámos também um modelo modificado geneticamente, onde identificamos uma alteração nos comportamentos sociais e hierarquias sociais.

A estratificação hierárquica é um fenómeno presente em quase todos os animais sociais, e pensa-se que pode promover um equilíbrio entre o partilhar de recursos e a minimização de lutas dentro do grupo social. Contudo, a posição na hierarquia social influência a saúde do individuo e particularmente em humanos, a posição na hierarquia social desempenha um papel crítico em prever os riscos associados ao desenvolvimento de problemas do foro respiratório, cardiovascular, inflamatório e psiquiátrico.

Os nossos resultados mostraram que o receptor NPY1r e a sua expressão no córtex pré-frontal desempenha um papel crítico na resposta as API. Descobrimos que animais sujeitos a API sofrem alterações a nível do sistema inibitório no córtex pré-frontal e caraterizámos as alterações de expressão génica nessa região cerebral (Franco et al. 2020, Neuropsychopharmacology 5-year IF IF= 6.777).

Descobrimos também que o gene GPRASP2, quando mutado, influencia os comportamentos sociais e a dominância social, tornando os animais hiper-dominantes. Dissecamos o mecanismo molecular de actuação do gene GPRASP2 como um modelador dos receptors metabotrópicos de glutamato (Edfawy et al. 2019, Nature Communications 5-year IF= 13.811).

Existem ainda dois trabalhos em preparação para publicação associados a este trabalho.

Esta investigação foi premiada com o Prémio Pfizer 2019 | Sociedade de Ciências Médicas de Lisboa, atribuído na categoria de Investigação Básica ao Dr. João Peça, PI do projecto “WINorLose”.

Publicizing Sheet
 

Franco, L. O., Carvalho, M. J., Costa, J., Ferreira, P. A., Guedes, J. R., Sousa, R., Edfawy, M., Seabra, C. M., Cardoso, A. L., & Peça, J. (2020). Social subordination induced by early life adversity rewires inhibitory control of the prefrontal cortex via enhanced Npy1r signaling. Neuropsychopharmacology, 10.1038/s41386-020-0727-7. Advance online publication. https://doi.org/10.1038/s41386-020-0727-7

Barros-Viegas, A. T., Carmona, V., Ferreiro, E., Guedes, J., Cardoso, A. M., Cunha, P., Pereira de Almeida, L., Resende de Oliveira, C., Pedro de Magalhães, J., Peça, J., & Cardoso, A. L. (2020). miRNA-31 Improves Cognition and Abolishes Amyloid-β Pathology by Targeting APP and BACE1 in an Animal Model of Alzheimer’s Disease. Molecular therapy. Nucleic acids, 19, 1219–1236. https://doi.org/10.1016/j.omtn.2020.01.010

Catarina M Seabra, Ana Rafaela Oliveira, Joana R Guedes, Ana Luisa Cardoso, Diana B Sequeira, Paulo J Palma, Joao Miguel Santos, Frederico Duque, Guiomar Oliveira, Joao Peca (2020) Modeling the neurogenetics of neurodevelopmental disorders-hints from brain organoids. Proceedings of the 23rd Annual Meeting of the Portuguese Society of Human Genetics, Medicine: February 2020 – Volume 99 – Issue 9 – p e19291 doi: 10.1097/MD.0000000000019291

Luís F. Ribeiro, Tatiana Catarino, Mário Carvalho, Sandra D. Santos, Luísa Cortes, Patricio O. Opazo, Lyn Rosenbrier Ribeiro, Daniel Choquet, José A. Esteban, João Peça, Ana Luísa Carvalho (2020) Constitutive ghrelin receptor activity modulates AMPA receptor traffic and supports memory formation. bioRxiv 2020.02.05.934463; doi: https://doi.org/10.1101/2020.02.05.934463

Lima Caldeira, G., Peça, J., & Carvalho, A. L. (2019). New insights on synaptic dysfunction in neuropsychiatric disorders. Current opinion in neurobiology, 57, 62–70. https://doi.org/10.1016/j.conb.2019.01.004

Costa, J., Guedes, J., Ferreira, P., Franco, L., Peca, J., & Cardoso, A. L. (2019, July). Early life stress causes behaviour changes and microglia dysfunction in the pre-frontal cortex of male mice. In Glia (Vol. 67, pp. E529-E530). 111 RIVER ST, HOBOKEN 07030-5774, NJ USA: WILEY.

Rebelo, C., Pinho, S., Reis, T., Saraiva, C., Guedes, J., Bernardino, L., Peca, J. & Ferreira, L. (2019, April). NIR-light dependent delivery of Cre recombinase: an optogenetic tool for DNA modulation in the brain. In European Journal of Clinical Investigation (Vol. 49, pp. 165-165). 111 RIVER ST, HOBOKEN 07030-5774, NJ USA: WILEY.

Edfawy, M., Guedes, J. R., Pereira, M. I., Laranjo, M., Carvalho, M. J., Gao, X., Ferreira, P. A., Caldeira, G., Franco, L. O., Wang, D., Cardoso, A. L., Feng, G., Carvalho, A. L., & Peça, J. (2019). Abnormal mGluR-mediated synaptic plasticity and autism-like behaviours in Gprasp2 mutant mice. Nature communications, 10(1), 1431. https://doi.org/10.1038/s41467-019-09382-9

Sequeira DB, Seabra CM, Palma PJ, Cardoso AL, Peça J, Santos JM. Effects of a New Bioceramic Material on Human Apical Papilla Cells. J Funct Biomater. 2018;9(4):74. Published 2018 Dec 16. doi:10.3390/jfb9040074

Santos, T., Ferreira, R., Quartin, E., Boto, C., Saraiva, C., Bragança, J., Peça, J., Rodrigues, C., Ferreira, L., & Bernardino, L. (2017). Blue light potentiates neurogenesis induced by retinoic acid-loaded responsive nanoparticles. Acta biomaterialia, 59, 293–302

Peça, J., & Feng, G. (2012). Cellular and synaptic network defects in autism. Current opinion in neurobiology, 22(5), 866-872.

*Ting, J. T., *Peça, J., & Feng, G. (2012). Functional consequences of mutations in postsynaptic scaffolding proteins and relevance to psychiatric disorders. Annual review of neuroscience, 35, 49-71.

Peça, J., Ting, J., & Feng, G. (2011). SnapShot: autism and the synapse. Cell, 147(3), 706-706.

Peça, J., & Feng, G. (2011). When lights take the circuits out. Nature, 477(7363), 165-166.

Peça, J., Feliciano, C., Ting, J. T., Wang, W., Wells, M. F., Venkatraman, T. N., Lascola, C. D., Fu, Z., & Feng, G. (2011). Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature, 472(7344), 437–442. https://doi.org/10.1038/nature09965

Heyer, M. P., Feliciano, C., Peca, J., & Feng, G. (2011). Elucidating gene function through use of genetically engineered mice. Genomics. John Wiley & Sons, Ltd, 211-248.

Arenkiel, B. R., & Peca, J. (2009). Using light to reinstate respiratory plasticity. Journal of neurophysiology, 101(4), 1695-1698.

Welch, J. M., Lu, J., Rodriguiz, R. M., Trotta, N. C., Peca, J., Ding, J. D., Feliciano, C., Chen, M., Adams, J. P., Luo, J., Dudek, S. M., Weinberg, R. J., Calakos, N., Wetsel, W. C., & Feng, G. (2008). [SY5. 1]: Synaptic and circuitry mechanisms of obsessive compulsive‐like behaviors in mice. International Journal of Developmental Neuroscience, 26(8), 835-835.

Welch, J. M., Lu, J., Rodriguiz, R. M., Trotta, N. C., Peca, J., Ding, J. D., Feliciano, C., Chen, M., Adams, J. P., Luo, J., Dudek, S. M., Weinberg, R. J., Calakos, N., Wetsel, W. C., & Feng, G. (2007). Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice. Nature, 448(7156), 894–900. https://doi.org/10.1038/nature06104

*Wang, H., *Peca, J., *Matsuzaki, M., Matsuzaki, K., Noguchi, J., Qiu, L., Wang, D., Zhang, F., Boyden, E., Deisseroth, K., Kasai, H., Hall, W. C., Feng, G., & Augustine, G. J. (2007). High-speed mapping of synaptic connectivity using photostimulation in Channelrhodopsin-2 transgenic mice. PNAS, 104(19), 8143–8148. https://doi.org/10.1073/pnas.0700384104

Arenkiel, B. R., Peca, J., Davison, I. G., Feliciano, C., Deisseroth, K., Augustine, G. J., Ehlers, M. D., & Feng, G. (2007). In vivo light-induced activation of neural circuitry in transgenic mice expressing channelrhodopsin-2. Neuron, 54(2), 205–218. https://doi.org/10.1016/j.neuron.2007.03.005