My memory of Paul

Throughout our lives, we are accompanied by various needs, both physical and spiritual, which each of us tries to fulfill to make life better and more complete. One of these needs is to meet a teacher, a mentor, someone who shows us how to live and work; a person we look up to and strive to follow. For me, without a shadow of a doubt, a person like this was Paul Willner. I met Paul over 30 years ago when I came to his Department of Psychology at the City of London Polytechnic to work as a post-doc. The 3 years I spent in London were extremely intense and productive. It was my first stay in the country behind the Iron Curtain, and the research we conducted then was far different, both in quantity and quality, from what I was used to at my home institute. And, it was during this stay in London that Paul taught me everything that is important in the work of a scientist, thus shaping my entire future professional life. Paul was not an easy boss, demanding a lot, but at the same time extremely inspiring. One of the ways of conducting scientific work that I remember particularly well was the brainstorming sessions that he often organized for us. As a result, new solutions and ideas were created, which we later implemented. Sometimes there were a bit too many ideas for the relatively small team we had at the time but Paul was by no means concerned about our excessive responsibilities. The result of this intensive work was 14 publications, which was quite an achievement for those times. Paul wrote with ease, in beautiful English, without unnecessary baroque elements or stylistic overload. His arguments were logical, although not understandable to everyone because they required a lot of concentration, and his conclusions were intellectually flawless. One of the main scientific issues that we dealt with at that time was the implementation and validation of the chronic mild stress (CMS) procedure, which Paul invented and introduced to his laboratory. The development of this animal model of depressive disorder and its subsequent acceptance by scientific community was of fundamental importance for expanding knowledge about the mechanisms of depression and antidepressant action, and also contributed significantly to the development of new antidepressant drugs. We all thought that having such a procedure, which seemed to fully meet the construct, face, and predictive validity required for an animal model of human disease, would quickly lead to understanding depression and antidepressant action. Now, after 3 decades of research using this model, I am much less optimistic. Paul was passionate about science, so work on optimizing the CMS procedure as a model of depression and its validation was not the only project that was being conducted in his laboratory at that time (e.g. a series of studies on the role of dopamine and its receptors in rewarded behavior). However, I did not participate in them, so I will not write about them here. After returning to my country, I continued research using the CMS model and continued to maintain contact with Paul, although somewhat less intensively. Nevertheless, even then we often contacted each other, discussed and exchanged opinions on various aspects of our private and professional lives. In the early 2000s, we reestablished close scientific cooperation and for the next 2 decades, we conducted joint studies, among others within the framework of four jointly prepared grants, on the brain processes underlying depression and the neuropathology underlying resistance to antidepressant drugs, and mechanisms by which adjunctive stimulation of some neural systems can overcome treatment resistance. This problem seemed to us particularly important in the present times. Major depression is the leading cause of global disease burden, with over 300 million sufferers. The most severely disabled group are those with treatment-resistant depression (TRD), who comprise more than half of the total. Therefore, explaining the processes associated with insensitivity to antidepressant therapy has significant translational significance because it may consequently reduce the suffering of many people with TRD. In these studies, we used an animal model of drug-resistant depression developed earlier together: the CMS procedure applied to Wistar–Kyoto rats. These rats do not respond to traditional antidepressants, which we confirmed by showing the lack of effect of imipramine, venlafaxine, and citalopram. On the other hand, single applications of DBS in the medial prefrontal cortex and similar peripheral and intracortical microinfusions of ketamine caused a potent, rapid, and long-lasting normalization of emotional and cognitive deficits induced by chronic stress. Having thus a valid model of TRD, we began a series of studies using optogenetic stimulation and inhibition of selected brain structures to attempt to reveal behavioral and neurochemical differences between the effects of antidepressants and DBS in animals that did not respond to the drugs, and similarities between effects of drugs in animals that responded and the effect of DBS in animals that did not respond to antidepressants. The results of these studies allowed us to formulate a number of hypotheses that significantly expanded our knowledge of the studied mechanisms and were presented in over 20 publications. One of the main hypotheses was that resistance to antidepressant drug treatment results from structural and functional abnormalities within the ventral hippocampus of treatment-resistant individuals, and that treatments that are effective in TRD activate the medial prefrontal cortex and its output pathways, bypassing the compromised HPC. Once again, this was a very busy and productive period in my life. We regularly organized videoconferences during which we discussed planned projects, analyzed the obtained results, and prepared further publications. Recently, we prepared and obtained another grant, in which we intended to start mapping out pathways in the brain where stimulation can overcome resistance to treatment with the antidepressants in WKY rats. Unfortunately, Paul’s death interrupted this beautiful time, but oh well, life goes on. We come, we go, while Paul seemed eternal. And, he will remain eternal in my memory. I will end this short eulogy with a Hebrew proverb: let us not say in grief that he is gone, but say in thankfulness that he was. Acknowledgements Conflicts of interest There are no conflicts of interest.