Univ.-Prof. Dr. Tibor Harkany
The Harkany lab has three major lines of research. Firstly, we address the developmental mechanisms by which cellular heterogeneity is established in the central nervous system, particularly in the neuroendocrine command modules of the hypothalamus. Secondly, we aim to understand entry points of cellular vulnerability upon maternal life-style changes, particularly food preference and illicit drug use, and the molecualr encoding of long-lasting transgenerational modifications to neuronal circuits. Thirdly, we continue to study adverse modifications to endocannabinoid and neuropeptide signaling upon maternal cannabis exposure during pregnancy.
Focal points of interest
The Harkany lab has worked on the development of GABA neurons in relation to neurotrophin and endocannabinoid signalins for over two decades, with early work published in 2003—2005. We have particularly elucidated that neurotrophin receptors use endocannabinoids as downstream effectors of neuronal differentiation. Later work on cortical GABA interneurons established ‘Patch-seq’ as the most advanced cell porfiling tool integrating patch-clamp electrophysiology and single-cell RNA-seq, and helped to reclassify (and subclassify) many lesser-known interneuron subtypes. More recently, we have used large-scale single-cell RNA-seq to chart developmental trajectories and end-state identities for neurons and glia in the developing and adult hypothalamus, respectively. These studies defined the design logic of neuroendocrine centers, and describe their specific vulnerabilities to diverse adverse/harmful stimuli during brain development.
Technical proficiency and instrumentation
The Harkany lab uses a multidisciplinary approach, with single-cell biology (transcriptome, epigenome sequencing, spatial transcriptomics) being its usual starting point. Experimental research then utilizes both in vitro and in vivo models in non-mammalian and mammalian organisms. As read-outs, we use imaging, protein biochemistry, and patch-clamp electrophysiology. Neuroendocrine, metabolic, and behavioral profiling in conjunction with chemogenetic and optogenetic manipulations are common end-points, particularly when testing causality between cell types and motivated behaviors. In addition, the laboratory has a strong history of neuroanatomy to analyze the structure of neuronal circuits, recently relying on virus-based circuit mapping methods. Finally, our projects emphasize human relevance (both in physiological and pathobiological contexts). Therefore, we extensively rely on human neuropathology to extrapolate our findings in experimental models to the human nervous system.
Aspirations for the next 5 years
For the next five years, and within the framework of this Cluster of Excellence, we will examine how GABA cell diversity and allocation to specific hypothalamic nuclei is mandated during brain development. Considering that GABA neurons desitned to the hypothalamus undergo sequential cell-state decisions, some charaterized by pleitoropic neuropeptide expression patterns, we will address neuropeptide functions, including both specificity and redundancy, in shaping hypothalamic circuit establishment. We will take advantage of the evolutionarily conservation of the hypothalamus to compare, across vertebrate species, how neurocircuit layouts, particularly cascading GABA neuron diversification, impinge on operational decisions, and the fidelity of neuroendocrine output during circadian and seasonal timescales. Lastly, we will continue to explore how maternal drug abuse during pregnancy affects GABA neurons of the fetal brain, and if genetic modifications (editing) to GABA neurons could offer rescue to life-long neuroendocrine impairments.
References
- Benevento M, Alpár A, Gundacker A, Afjehi L, Balueva K, Hevesi Z, Hanics J, Rehman S, Pollak DD, Lubec G, Wulff P, Prevot V, Horvath TL, Harkany T. A brainstem-hypothalamus neuronal circuit reduces feeding upon heat exposure. Nature 2024; 628(8009): 826-834. doi: 10.1038/s41586-024-07232-3.
- Romanov RA, Tretiakov EO, Kastriti ME, Zupancic M, Häring M, Korchynska S, Popadin K, Benevento M, Rebernik P, Lallemend F, Nishimori K, Clotman F, Andrews WD, Parnavelas JG, Farlik M, Bock C, Adameyko I, Hökfelt T, Keimpema E, Harkany T. Molecular design of hypothalamus development. Nature 2020; 582(7811): 246-252. doi: 10.1038/s41586-020-2266-0.
- Alpár A, Zahola P, Hanics J, Hevesi Z, Korchynska S, Benevento M, Pifl C, Zachar G, Perugini J, Severi I, Leitgeb P, Bakker J, Miklosi AG, Tretiakov E, Keimpema E, Arque G, Tasan RO, Sperk G, Malenczyk K, Máté Z, Erdélyi F, Szabó G, Lubec G, Palkovits M, Giordano A, Hökfelt TG, Romanov RA, Horvath TL, Harkany T. Hypothalamic CNTF volume transmission shapes cortical noradrenergic excitability upon acute stress. EMBO J. 2018; 37(21):e100087. doi: 10.15252/embj.2018100087.
- Fuzik J, Zeisel A, Máté Z, Calvigioni D, Yanagawa Y, Szabó G, Linnarsson S, Harkany T. Integration of electrophysiological recordings with single-cell RNA-seq data identifies neuronal subtypes. Nat Biotechnol. 2016; 34:175-183. doi: 10.1038/nbt.3443.
