20.500.12556/RUL-182417 Ultrasonic vocalizations as a measure of anhedonia in a rat model of endogenous depression research data underlying the doctoral dissertation Ultrazvočne vokalizacije kot merilo anhedonije pri podganjem modelu endogene depresije raziskovalni podatki, obravnavani v doktorskem delu Anhedonia is a core symptom of depression, defined as a diminished interest in stimuli or a diminished pleasure in response to stimuli that were previously perceived as rewarding. Current and novel antidepressant treatments notably underperform in alleviating anhedonia. The problem potentially stems from imprecise assessments of anhedonia that merge disrupted motivational (wanting) and consummatory (liking) aspects of reward experience. Therefore, precise experimental tools for the measurement of anhedonia in preclinical models are needed. To tackle this research gap, ultrasonic vocalizations (USVs) related to rewarding stimuli (amphetamine (AMPH)/ morphine (MORPH)) were measured and compared to standard measurements of anhedonia. Two rat lines were compared: the Wistar-Kyoto line (WKY, model of endogenous depression) and the Wistar line (W, control line). 50-kHz USVs were recorded in response to the first and last drug administration, and in anticipation of the last drug administration. Comparable behavioural measures were collected: drug-related locomotor activity, sucrose intake in the sucrose preference test (SPT) two times, and approach behaviour in the conditioned place preference (CPP) paradigm. Post-mortem, molecular markers for anhedonia (BDNF) and addiction (ΔFosB) were assessed in three brain regions involved in the reward circuit: prefrontal cortex (PFC), nucleus accumbens (NAc), and ventral tegmental area (VTA). All molecular data were assessed with adjusted band density acquired with Western Blot, count of mRNA-positive cells acquired by in-situ hybridization, and count of immunoreactive cells acquired by immunohistochemistry. Behaviourally, WKY rats emitted less 50-kHz USVs and crossed less distance in response to the first and last AMPH administration. WKY rats also showed divergence between USVs and locomotor responses during repeated treatment. Contrary to W rats, WKY rats exhibited sensitization of USVs. No differences between treatments were observed in the anticipatory situation. Sucrose intake in the SPT was reduced in the WKY line. No approach behaviour was observed in the CPP. BDNF levels were elevated in the WKY line for all three regions of interest. ΔFosB levels were elevated in the PFC of the WKY line. In conclusion, 50-kHz USVs showcase reduced reward response in the WKY line, evidenced by comparable behavioural measures and BDNF expression in the reward circuit. Anhedonija je osrednji simptom depresije, opredeljena kot zmanjšan interes za dražljaje ali zmanjšan užitek v odzivu na dražljaje, ki so bili prej dojemani kot nagrajujoči. Sedanja in nova antidepresivna zdravljenja so pri lajšanju anhedonije premalo učinkovita. Problem verjetno izhaja iz netočnih ocen anhedonije, ki združujejo motene motivacijske (želja) in konsumativne (užitek) vidike izkušnje nagrajevanja. Zato so potrebna natančna eksperimentalna orodja za merjenje anhedonije v predkliničnih modelih. Za to namen so bile izmerjene ultrazvočne vokalizacije (USV), povezane z nagradnimi dražljaji (amfetamin (AMPH) /morfin (MORPH)), in primerjane s standardnimi meritvami anhedonije. Primerjali smo dve liniji podgan: linijo Wistar-Kyoto (WKY, model endogene depresije) in linijo Wistar (W, kontrolna linija). 50-kHz USV-je smo posneli kot odziv na prvo in zadnje nagrajevanje ter v pričakovanju zadnjega nagrajevanja. Zbrane so bile primerljive vedenjske meritve: lokomotorična aktivnost povezana z drogami, dvakratno merjenje vnosa sukroze v testu preference sladkorja (SPT) in približevanje v paradigmi pogojene preference prostora (CPP). Po evtanaziji so bili ocenjeni molekularni markerji za anhedonijo (BDNF) in odvisnost (ΔFosB) v treh možganskih regijah, vključenih v nagrajevalni krog: prefrontalni korteks (PFC), nucleus accumbens (NAc) in ventralno tegmentalno območje (VTA). Vsi molekularni podatki so bili ocenjeni na podlagi prilagojene gostote pasov, pridobljene z metodo Western Blot, števila celic, pozitivnih na mRNA, pridobljenega z in situ hibridizacijo, ter števila imunoreaktivnih celic, pridobljenega z imunohistokemijo. Pri vedenju so podgane WKY oddajale manj 50-kHz USV-jev in prehodile krajšo razdaljo v odzivu na prvo in zadnje nagrajevanje z AMPH. Podgane WKY so med ponavljajočim tretmanom pokazale tudi razlike med USV-ji in lokomotornimi odzivi. V nasprotju s podganami W so podgane WKY pokazale sensitizacijo USV-jev. V situaciji pričakovanja niso bile opazne razlike med tretmani. Vnos sukroze v SPT je bil zmanjšan v liniji WKY. V CPP ni bilo opaziti nobenega približevanja. Ekspresija BDNF-a je bila v liniji WKY povišana v vseh treh regijah. Ekspresija ΔFosB-ja je bila povišana v PFC-ju linije WKY. Končno, 50-kHz USV-ji kažejo zmanjšan odziv na nagrado v liniji WKY, kar dokazujejo primerljive vedenjske meritve in izražanje BDNF v možganski poti nagrajevanja. 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