Parenting and depression-like behaviour are both driven by preoptic GABAergic neurons in mice
Diana Dimen1, Gina Puska1, Eszter Sipos2, Veronika Csillag3, Imre Farkas4, Dora Zelena2, Arpad Dobolyi1
1 MTA-ELTE Laboratory of Molecular and System Neurobiology, Department of Physiology and Neurobiology, Hungarian Academy of Science and Eötvös Loránd University, Budapest, Hungary
2 Department of Behavioral Neuroscience, Institute of Experimental Medicine, Budapest, Hungary
3 Department of Endocrine Neurobiology, Institute of Experimental Medicine and Roska Tamás Doctoral School of Sciences and Technology, Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, Budapest, Hungary
4 Laboratory of Reproductive Neurobiology, Institute of Experimental Medicine, Budapest, Hungary
Preoptic neurons, activated by pup exposure in dams, contain the inhibitory neurotransmitter GABA based on traditional double-labelling techniques. We hypothesized that preoptic GABA-positive neurons mediate maternal behavioural changes. Firstly, c-Fos immunohistochemistry using VGAT-ZsGreen reporter mouse line was performed, which confirmed the pup-dependent activity of GABAergic neurons located in the preoptic region in mother and sensitized virgin female mice, but not in male mice. To understand the function of GABA-positive preoptic neurons in parenting, we performed cell-type-specific chemogenetic manipulation in freely moving VGAT-Cre animals. The selective stimulation of preoptic GABAergic neurons caused intense caring behaviour in female mice, and pup-directed aggression in male mice. In addition, we found a strong positive correlation between pup-associated motivated behaviour and depression-like behaviour (measured by forced-swim and sucrose preference tests) in both sexes. These findings suggest that the preoptic inhibitory neurons govern the parenting and depression-like behaviours simultaneously. Furthermore, we identified the projections of the preoptic GABAergic neurons by whole-brain mapping to determine their neuronal outputs. One of the major inputs of preoptic area is provided by tuberoinfundibular peptide of 39 (TIP39), previously identified as a parentally induced thalamic neuropeptide abundant in preoptic fibres terminals. Measured by in vitro brain slice electrophysiology, TIP39 increased the firing rate of preoptic GABAergic neurons dose-dependently, an effect eliminated by an antagonist of the receptor of TIP39. In conclusion, this study established the importance of preoptic GABA-positive neurons as a key node in the neuronal network underlying maternal care and point out the sexual dimorphic control of parenting by the same group of neurons. Moreover, we provide novel insight into the connection between pup-associated motivated behaviour and depression-like behaviour. Grant support: NKFIH-4300-1/2017-NKP_17 (NAP2), NKFIH-OTKA K116538.