mirCOS

Micro-RNA & Social Cognition

Humans are intrinsically social beings. We live in a world that is largely socially constructed and our lives are replete with social interactions everyday. Thus, while other high-order brain functions (i.e. abstract thinking) are used for brief periods of time during our daily life, social network is experienced almost constantly. Human brain is therefore designed to constantly monitor our social environment, to efficiently process social cues and to generate adaptive social behaviors. Although recent technological advances (i.e. brain imaging) have contributed to the identification of brain circuits/areas linked to social activities, how social processes are controlled at the molecular level remains largely unexplored.

Human brain areas involved in different domains of socially related behaviors (Riitta Hari, Miiamaaria V. Kujala Physiological Reviews 2009)

MicroRNAs (miRNAs) are short (20-25 nucleotides) non-coding RNAs that post-transcriptionally regulate gene expression. Since their discovery, miRNAs have been implicated in most biological functions (Jonas S and Izaurralde E. Nat Rev Genet. 2015). Mechanistically, miRNAs recognize and bind to 6-8 nt target sequences present in mRNAs (most often in untranslated regions). miRNA-mRNA interactions result in transcript degradation, translation inhibition or both leading to gene silencing. miRNAs have attracted much attention because of their combinatorial mode of action. Recognition sequence for a particular miRNA could be found in tens of transcripts. Similarly, a single transcript can contain target sequences for multiple miRNAs. Consequently, a single miRNA could target multiple genes (multiplicity) and several miRNAs contribute to regulate the expression of the same target (cooperativity). In this way, miRNAs networks are thought to finely tune gene expression (Herranz and Cohen, Genes Dev 2010).

Basic mechanisms of miRNA action (From Small and Olson Nature 2012)

Although accumulating evidence indicates that miRNAs might be essential for complex brain functions, the relationship between microRNA regulation and the specification of behavior is only beginning to be explored. . First, evolutionary data suggest that increasing brain complexity is not related to coding gene number but to the ability to generate novel patterns of gene expression (Taft et al., Bioessays 2007). In this line, it has been shown miRNAs families have considerably expanded along evolution. Moreover, most recent miRNAs (in evolutionary terms) are enriched or exclusively expressed in the brain supporting the contention that miRNAs evolution paralleled the development of increasingly sophisticated brains (Berezikov et al. Nat Gen. 2006). Second, neurons might take fully advantage of the combinatorial power of miRNAs networks. By modulating translation and/or stability of a large number of mRNA targets in a coordinated and cohesive fashion, miRNAs have the capability to integrate the myriad of incoming signals simultaneously impinging on a neuron. Third, individual miRNAs have been shown to modulate specific aspects of brain function such as drug intake or sociability without affecting other behaviors (Hollander et al. Nature 2010; Gascon et al. Nat Med 2014). Finally and in the same line, different brain pathologies (i.e. Alzheimer disease or major depressive disease) are associated to distinct alterations of miRNAome (Szafranski et al., Front Genet 2015) indicating that alterations of miRNAs might be at the origin of brain dysfunctions.

The main goals of our lab are:

  • 1. To identify those miRNAs involved in the molecular control of specific domains of mouse behavior. We are particularly interested in those miRNAs linked to social behavior (social miRNAs) and motor control (motor miRNAs). Additionally, we will explore the neuronal networks (brain regions and neuronal subsets) implicated in those behaviors.
  • 2. To investigate the neuronal mechanisms regulated by social miRNAs. This includes molecular (i.e. downstream targets of social miRNAs), cellular (i.e. morphological changes in dendrites/axons) and electrophysiological (i.e. synaptic plasticity).
  • 3. To study the molecular pathways by which aging affects miRNAs homeostasis.

In order to address these challenging issues, we combine a number of experimental approaches both in vivo (using mice as experimental model) and in vitro (cell lines, neuronal cultures and slices). In addition, we are applying a wide range of techniques, from molecular (i.e. cloning, quantitative RT-PCR or northern blot for miRNAs) and cellular biology (i.e. transfection, FACS or imaging) to electrophysiology and behavioral testing. Finally, we are taking advantage of the state-of-the-art technology in genome editing (CRISPR-Cas9) and adeno-associated vectors (AAV) design.

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