Neuromodulation of Cognition

Research focus

Approach or avoidance are fundamental ways we interact with the world around us, to ensure safety and meet our survival needs. The locus coeruleus (LC), the brain’s primary source of norepinephrine (NE), provides far-reaching innervation that ensures rapid and targeted NE release in response to ever-changing environments. By doing so, the LC coordinates the neurocognitive processes that guide our behavior under approach or avoidance conflicts, dictating adaptive responses to uncertainty. As such, dysregulation of the LC NE system is linked to a multitude of interrelated pathological states, including anxiety, attentional and impulse control disorders.

Collectively, our research aims to unravel the neuromodulatory influences arriving to and exerted by the LC, that ensure optimal behavioral responses to challenging environments (e.g., adversity, stress, high cognitive demand). For this, we follow two major research trajectories, investigating:

1. What are the endogenous modulatory systems that fine-tune LC activity? We focus on LC neuropeptides and their receptors, and how peptidergic signalling modulates LC function during complex behaviors.
2. How does NE-mediated signalling alter cognition-associated circuits? We focus on distinct LC neuronal ensembles, and how modular neural communication to LC efferents sculps cognitive function.

Together, we probe LC function both in terms of its regulation, i.e., LC neuromodulation by peptidergic inputs, and the consequences of that, i.e., neuromodulation of output (target) regions following NE release.

Methodology

We aim to bring mechanistic insights to complex behaviors, thus, we employ a multifaceted methodological approach, that spans from the individual synapse to the intact animal. In particular, we use intersectional (viral & genetic) strategies for identification and manipulation of LC NE and/or peptidergic neuronal clusters. We complement this with opto-/chemogenetics-coupled slice electrophysiology that enables interrogation of functional connectivity in relevant circuits. Further, we employ synaptic proteomics to map the molecular architecture of the LC NE system, and its input-output landscape. Finally, we implement in-vivo imaging for monitoring NE and peptidergic dynamics, as well as in-vivo (e.g., pharmacological, pharmacogenetic) interventions to examine the causal links between neuromodulatory signalling and (mal)adaptive behaviors.

Open positions

We are looking for a PhD student, to join us by spring 2025. Master students are welcome to apply for an internship in the lab. If you are interested in our research, please reach out with your ideas and input. We are always happy to discuss hiring possibilities with motivated candidates.

For the latest lab news, please check Twitter/X @dan_ai_lama

Ongoing collaborations

Science does not happen in a vacuum. We are proud that the team is embedded in a lively and collaborative environment, at Amsterdam Neuroscience. Here, we join forces with the teams of Dr. Rao-Ruiz (Molecular Engrams) and Dr. Michel van den Oever (Memory Circuits). In addition, we retain strong ties with the lab of Dr. Frank Meye at Utrecht UMC.

Selected Publications

Riga D, Rademakers K, Wolterink-Donselaar IG, Meye FJ. Neuropeptide Y neurons of the locus coeruleus inhibit noradrenergic system activity to reduce anxiety. [bioRxiv preprint]. 2023 October. doi: 10.1101/2023.10.16.562534.

Linders LE, Supiot LF, Du W, D’Angelo R, Adan RAH, Riga D, Meye FJ. Studying Synaptic Connectivity and Strength with Optogenetics and Patch-Clamp Electrophysiology. Int J Mol Sci. 2022 Oct 1;23(19). doi: 10.3390/ijms231911612. Review. PubMed PMID: 36232917; PubMed Central PMCID: PMC9570045.

van de Haar LL, Riga D, Boer JE, Garritsen O, Adolfs Y, Sieburgh TE, van Dijk RE, Watanabe K, van Kronenburg NCH, Broekhoven MH, Posthuma D, Meye FJ, Basak O, Pasterkamp RJ. Molecular signatures and cellular diversity during mouse habenula development. Cell Rep. 2022 Jul 5;40(1):111029. doi: 10.1016/j.celrep.2022.111029. PubMed PMID: 35793630.

Spijker S, Koskinen MK, Riga D. Incubation of depression: ECM assembly and parvalbumin interneurons after stress. Neurosci Biobehav Rev. 2020 Nov;118:65-79. doi: 10.1016/j.neubiorev.2020.07.015. Epub 2020 Jul 17. Review. PubMed PMID: 32687884.

Riga D, Kramvis I, Koskinen MK, van Bokhoven P, van der Harst JE, Heistek TS, Jaap Timmerman A, van Nierop P, van der Schors RC, Pieneman AW, de Weger A, van Mourik Y, Schoffelmeer ANM, Mansvelder HD, Meredith RM, Hoogendijk WJG, Smit AB, Spijker S. Hippocampal extracellular matrix alterations contribute to cognitive impairment associated with a chronic depressive-like state in rats. Sci Transl Med. 2017 Dec 20;9(421). doi: 10.1126/scitranslmed.aai8753. PubMed PMID: 29263233.

Riga D, Matos MR, Glas A, Smit AB, Spijker S, Van den Oever MC. Optogenetic dissection of medial prefrontal cortex circuitry. Front Syst Neurosci. 2014;8:230. doi: 10.3389/fnsys.2014.00230. eCollection 2014. Review. PubMed PMID: 25538574; PubMed Central PMCID: PMC4260491.

Riga D, Schmitz LJ, van der Harst JE, van Mourik Y, Hoogendijk WJ, Smit AB, De Vries TJ, Spijker S. A sustained depressive state promotes a guanfacine reversible susceptibility to alcohol seeking in rats. Neuropsychopharmacology. 2014 Apr;39(5):1115-24. doi: 10.1038/npp.2013.311. Epub 2013 Nov 6. PubMed PMID: 24192553; PubMed Central PMCID: PMC3957105.

Wouda JA, Diergaarde L, Riga D, van Mourik Y, Schoffelmeer AN, De Vries TJ. Disruption of Long-Term Alcohol-Related Memory Reconsolidation: Role of β-Adrenoceptors and NMDA Receptors. Front Behav Neurosci. 2010;4:179. doi: 10.3389/fnbeh.2010.00179. eCollection 2010. PubMed PMID: 21152256; PubMed Central PMCID: PMC2998860.