Molecular and synaptic organization

Execution of complex behaviors such as social interactions relay on the integration of different signals arising from multiple brain areas. We are interested in understanding how these signals are integrated within the midbrain periaqueductal gray (PAG), a major interface between the forebrain and the lower brainstem that plays a major role in integrated innate behavioral responses, such as aggression and mating. We aim to characterize, in exquisite detail the molecular and synaptic organization of PAG circuits using a combination of single-cell transcriptional profiling, viral labelling and tracing of connectivity in genetically-defined PAG populations, as well as detailed electrophysiological characterization of these different cell types.

Neural circuits and behavior

The PAG is considered a major node for organization of innate social behaviors, but how different PAG neurons promote specific aspects of behavioral outputs remain poorly understood. We are using a combination of advanced video-tracking, recordings of ultrasonic vocalizations during naturalistic social interactions, cell-type specific manipulation of PAG circuits via chemo- and optogenetic approaches, and in vivo fiber photometry to dissect the contribution specific PAG neuronal populations to behavioral outputs.

Neuropsychiatric disorders

Disruption of innate social behaviors is commonly observed in devastating neuropsychiatric disorders such as autism, schizophrenia, and bipolar disorder. We aim to understand the genetic and circuits basis of neuropsychiatric disorders using two distinct but complementary approaches. First. We are capitalizing on emerging stem-cell and CRISPR technologies to introduce disease-relevant mutations in pluripotent cells prime to develop into human neurons, and study the effects at the genetic and synaptic level. Second. We are taking advantage of mouse models of neuropsychiatric diseases as well as state of the art circuit approaches to generate a comprehensive understanding of disease-associated changes in PAG cell-types and synaptic connections that may underlie, and ultimately promote, behavioral abnormalities during disease.

In 2021, we published our first paper from the lab (Mencacci et al, JCI 2021).

We furthermore received a grant from the Fritz Thyssen Stiftung to study how a presynaptic active zone protein called RIM1, contributes to autism pathogenesis. For this we use advanced CRISPR/cas9 technology in induced human neurons in vitro.

Publications after start of funding

Marcó de la Cruz B, Campos J, Molinaro A, Xie X, Jin G, Wei Z, Acuna C and Sterky FH (2024) Liprin-α proteins are master regulators of human presynapse assembly. Nature Neuroscience. Doi: 10.1038/s41593-024-01592-9

Huppertz MC, Wilhelm J, Grenier V, Schneider MW, Falt T, Porzberg N, Hausmann D, Hoffmann DC, Hai L, Tarnawski M, Pino G, Slanchev K, Kolb I, Acuna C, Fenk LM, Baier H, Hiblot J and Johnsson K (2024) Recording physiological history of cells with chemical labeling. Science 383:890-897. Doi: 10.1126/science.adg0812.

Ziegler K, Folkard R, Gonzalez AJ, Burghardt J, Antharvedi-Goda S, Martin-Cortecero J, Isaías-Camacho E, Kaushalya S, Tan LL, Kuner T, Acuna C, Kuner R, Mease RA and Groh A (2023) Primary somatosensory cortex bidirectionally modulates sensory gain and nociceptive behavior in a layer-specific manner. Nat Commun 14:2999. Doi: 10.1038/s41467-023-38798-7.

Weigel B, Tegethoff JF, Grieder SD, Lim B, Nagarajan B, Liu YC, Truberg J, Papageorgiou D, Adrian-Segarra JM, Schmidt LK, Kaspar J, Poisel E, Heinzelmann E, Saraswat M, Christ M, Arnold C, Ibarra IL, Campos J, Krijgsveld J, Monyer H, Zaugg JB, Acuna C and Mall M (2023) MYT1L haploinsufficiency in human neurons and mice causes autism-associated phenotypes that can be reversed by genetic and pharmacologic intervention. Mol Psychiatry 28:2122-2135. Doi: 10.1038/s41380-023-01959-7.

Koch J, Xin Q, Obr M, Schäfer A, Rolfs N, Anagho HA, Kudulyte A, Woltereck L, Kummer S, Campos J, Uckeley ZM, Bell-Sakyi L, Kräusslich HG, Schur FK, Acuna C and Lozach PY (2023) The phenuivirus Toscana virus makes an atypical use of vacuolar acidity to enter host cells. PLoS Pathog 19:e1011562. Doi:10.1371/journal.ppat.1011562.

Kapell H, Fazio L, Dyckow J, Schwarz S, Cruz-Herranz A, Mayer C, Campos J, D'Este E, Möbius W, Cordano C, Pröbstel AK, Gharagozloo M, Zulji A, Narayanan Naik V, Delank A, Cerina M, Müntefering T, Lerma-Martin C, Sonner JK, Sin JH, Disse P, Rychlik N, Sabeur K, Chavali M, Srivastava R, Heidenreich M, Fitzgerald KC, Seebohm G, Stadelmann C, Hemmer B, Platten M, Jentsch TJ, Engelhardt M, Budde T, Nave KA, Calabresi PA, Friese MA, Green AJ, Acuna C, Rowitch DH, Meuth SG and Schirmer L (2023) Neuron-oligodendrocyte potassium shuttling at nodes of Ranvier protects against inflammatory demyelination. J Clin Invest 133. Doi: 10.1172/JCI164223.

Plociennikowska A, Frankish J, Moraes T, Del Prete D, Kahnt F, Acuna C, Slezak M, Binder M and Bartenschlager R (2021) TLR3 activation by Zika virus stimulates inflammatory cytokine production which dampens the antiviral response induced by RIG-I-like receptors. J Virol 95. Doi: 10.1128/JVI.01050-20.

Mencacci NE, Brockmann MM, Dai J, Pajusalu S, Atasu B, Campos J, Pino G, Gonzalez-Latapi P, Patzke C, Schwake M, Tucci A, Pittman A, Simon-Sanchez J, Carvill GL, Balint B, Wiethoff S, Warner TT, Papandreou A, Soo A, Rein R, Kadastik-Eerme L, Puusepp S, Reinson K, Tomberg T, Hanagasi H, Gasser T, Bhatia KP, Kurian MA, Lohmann E, Õunap K, Rosenmund C, Südhof TC, Wood NW, Krainc D and Acuna C (2021) Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia. J Clin Invest 131. Doi: 10.1172/JCI140625.

Kamm GB, Boffi JC, Zuza K, Nencini S, Campos J, Schrenk-Siemens K, Sonntag I, Kabaoğlu B, El Hay MYA, Schwarz Y, Tappe-Theodor A, Bruns D, Acuna C, Kuner T and Siemens J (2021) A synaptic temperature sensor for body cooling. Neuron 109:3283-3297.e3211. Doi: 10.1016/j.neuron.2021.10.001.

Patzke C, Brockmann MM, Dai J, Gan KJ, Grauel MK, Fenske P, Liu Y, Acuna C, Rosenmund C and Südhof TC (2019) Neuromodulator Signaling Bidirectionally Controls Vesicle Numbers in Human Synapses. Cell 179:498-513.e422. Doi: 10.1016/j.cell.2019.09.011.