Research levels of investigation in our lab.
Mo­lecu­lar mech­an­isms of an­ti­de­press­ants

We have identified that antidepressant drugs increase TRKB phosphorylation and signaling (Castrén & Antila, 2018). Our recent research has identified a region within the transmembrane domain of TRKB that, when two TRKB monomers dimerize, forms a direct binding site of several antidepressant drugs, including the SSRI fluoxetine and the rapid-acting ketamine and its metabolite. We have also found that brain cholesterol plays a critical role in TRKB action and identified molecular and cellular mechanisms through which TRKB acts as a cellular cholesterol sensor. We are using biochemistry, molecular biology, advanced imaging, molecular modeling (in collaboration with Vattulainen lab), and behavioral studies to reveal the mechanisms or interactions of antidepressants and TRKB. Our findings have far-reaching implications for drug development and the understanding of antidepressant effects. 

Cel­lu­lar mech­an­ism of neuro­plas­ti­city

BDNF-TRKB signaling is critical for proper brain functioning at different levels, and impaired signaling has been shown to be associated with the etiology of stress-related mental illnesses and decreased plasticity. We aim to unveil the cellular and molecular processes that restrain TRKB signaling in order to identify potential therapeutic targets. Regulation of these targets could render the neuronal network more plastic and thus prone to recovery when associated with proper stimulation. We are particularly interested in the role of perineuronal nets/CSPGs components of the extracellular matrix and its receptor PTPRS (Receptor-type tyrosine-protein phosphatase S, PTPσ) upon TRKB dephosphorylation (Lesnikova et al, 2020). In parallel, we are also interested in the restraint of BDNF-TRKB signaling by nitric oxide through the nitration of tyrosine residues (Biojone et al, 2015). Furthermore, we are analyzing proteins that interact with TRKB and regulate its function, such as TRKB endocytosis by the AP2 complex (Fred et al., 2019). We make use of a variety of approaches, such as immunohistochemistry, analysis of protein expression and protein-protein interaction, structural bioinformatics, in vivo microscopy, and behavioral analysis, to investigate those questions at molecular and systemic levels.

Neuro­plas­ti­city on the net­work and sys­tem level

Although human understanding of the basic principles and structures in the brain has made significant progress, a deeper understanding of the principles and mechanisms that govern complex behavior (such as cognition, learning, or social behaviors) has remained very limited. System’s neuroscience is a new field that searches to bridge the gap between the cellular neuronal dynamics and complex behavior. The technology to perform long behavioral experiments while collecting neuronal data (either by electrophysiological recordings or imaging with calcium-indicators and Voltage-sensitive indicators) only came to fruition in the last decade, but huge advances have been made recently. Our lab aims to understand the networks and mechanisms underlying social behavior and addiction. We collect live data from the relevant brain structure, while the experiment is being performed. By doing so, we can try to untangle the connection between neuronal activity and the processing and execution of behavior in a way that was inaccessible beforehand.

Be­ha­vi­oral ef­fect of neuro­plas­ti­city mod­u­la­tion

Some kinds of interventions, including antidepressant and environmental enrichment, are known to induce a juvenile critical period-like plasticity (iPlasticity), where networks in the adult brain are allowed to better adapt to the changes in the internal and external milieu (reviewed in Umemori et al., 2018). Our group demonstrated that chronic treatment with the antidepressant fluoxetine combined with specific training or other external manipulations increases neural plasticity and alters symptoms of neuropsychiatric diseases in animal models of ocular dominance plasticity (Maya-Vetencourt et al. 2018), fear erasure (Karpova et al, 2011), and socialization (Mikics et al, 2018). The activation of the BDNF receptor TrkB is thought to be a key factor for iPlasticity, but it is unknown which neuronal circuits and how TrkB signaling modifies malformed networks resembled in the neuropsychiatric symptoms.

We currently use a photoactivatable TrkB (optoTrkB) (Chang et al., 2014) to activate TrkB spatially and temporally in certain subpopulations of neurons during behavioral experiments. With this tool and combination of antidepressant treatment with TrkB conditional knockout mice, we have so far shown that the activation of TrkB in Parvalbumin interneurons is necessary for visual cortex plasticity (Winkel et al., 2020), and in pyramidal neurons of ventral hippocampi promotes fear erasure (Umemori et al., submitted). We are also trying to apply these techniques to other behavioral paradigms, such as spatial reversal learning and extinction of drug addiction. We combine these with histological analysis, electrophysiology, and transcriptome to elucidate mechanisms of iPlasticity.

Neuro­plas­ti­city of en­vir­on­ment and so­cial mod­u­la­tion

Our everyday experiences can potentially enhance or inhibit our brain plasticity and consequently our ability to learn. Environment and experiences shape the brain structure and function and this theory is based on a long history of research. Rearing animals in an enriched environment (EE) has been reported to produce behavioral and biological changes that have consequently improved their cognitive performance, ameliorate abnormal behaviors, and reduced emotional reactivity. Adult brain plasticity is mediated by activity-dependent regulation of hippocampal neurogenesis with neurotrophin, BDNF, and neurotransmitter Serotonin playing major roles. We are looking for targeting molecules utilizing genetically modified and/or transgenic animals. Our findings could provide new insights regarding novel targets that could modulate adult brain plasticity and open treatment strategies for combinatorial therapy.