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The subthalamic nucleus (STN) is an important node in the basal ganglia circuitry. The developmental origin and molecular markers of STN have been adequately studied in animal models. However, there is a need to elucidate the molecular markers guiding the development of the human STN, as this nucleus is involved in the motor, associative, and limbic functions of the cortico-basal ganglia- thalamocortical circuitry. Moreover, some transcription factors identified in the STN of experimental animals are implicated in several neurodevelopmental disorders, but the structural and molecular changes of STN’s neuronal population in these disorders were never thoroughly explored. Aims The aim of the study was to identify spatio- temporal expression patterns of transcription factors relevant for the differentiation and specification of STN’s neuronal population. Methods This study encompassed postmortem, formalin-fixed, paraffin-embedded human fetal brain tissue from the early fetal period (12-15 post-conceptional weeks, PCW) to term. Indirect immunohistochemistry with antibodies for transcription factors FOXA1, FOXP1, FOXP2, BARHL1, and PAX6 was performed on 10µm thin sections. Results We show that the developing human STN expresses transcription factors previously shown to be involved in the development of rodent STN. Moreover, the human STN expresses some transcription factors that were not previously described in animal models. Conclusions Our preliminary study accentuates the need to study the transcription factors in the developing human STN because the results from animal models cannot fully predict the human STN’s molecular markers. Elucidating the STN’s transcriptional profile could advance our understanding of its functional properties and its role in neurodevelopmental disorders.

Subthalamic nucleus (STN) is a basal ganglia structure, clinically important as a target in the treatment for Parkinson's disease. Nkx2-1 is a transcription factor and, in the forebrain, a marker of neurons derived from medial ganglionic eminence (MGE) and hypothalamic basal plate. Nkx2- 1 is widely expressed in the subcortical forebrain, especially in the hypothalamus and the basal ganglia such as globus pallidus and striatum. STN is the most underexplored basal ganglia structure and its basic cytochemistry is still not fully described, neither in rodent models, nor in humans. The aim of this research is to investigate the expression of Nkx2-1 in the adult mouse, rat, and human STN. We used immunofluorescence and RNAscope to determine the expression of both Nkx2-1 mRNA and protein on adult FFPE mouse, rat, and human coronal brain slices containing STN. We reveal that the Nkx2-1 mRNA is present in all species’ STN, while Nkx2-1 protein is expressed only in the rat and human STN. The conclusion is that the Nkx2-1 mRNA is not translated into protein in the mouse STN, and this is a case of species-dependent posttranscriptional regulation of gene expression. The question remains what the functional significance of this finding is and why are the rat and human STN more similar in this parameter, when while looking at evolutionary relationships, this is expected from mouse and rat.

The subthalamic nucleus (STN) is a diencephalic structure which is an important part of the basal ganglia circuitry. As such, it has gained clinical interest as a target for deep brain stimulation treatment of Parkinson’s disease. Although it is a clinically relevant structure, little is known about its basic cytochemistry and phenotypical profile. When looking at the existing data, results from different species are often not overlapping and data from one species cannot be extrapolated to another. Because of this, we decided to do a systematic comparison between three species most commonly involved in STN research (human, mouse and rat) and compare the expression profiles of different transcription factors in the adult STN between the species. Our results show that there are many differences in the expression profiles of transcription factors between the three species, and that the STN is not strictly phenotypically conserved among them. Since transcription factors control many other downstream genes, differences in their expression suggest that there is a whole other spectrum of differences in the downstream genes, which raises a question of what is their functional significance, and why has it diverged in different mammals’ STN. Another concern is the fact that there are many experiments conducted with animal models of STN-related research and caution is needed in translating the results to humans since human and rodent STN might not quite be the same.

The subthalamic nucleus (STN) is one of the major output nuclei of the basal ganglia circuits. With the advancement of neurosurgical techniques for treatment of movement disorders, it has become necessary to explore the STN on a cellular and molecular level. Although the physiology and connectivity of the STN are welldescribed in model animals, cytoarchitecture, developmental origin, and molecular markers are still greatly underexplored, especially in humans. Developmental origin and transcriptional codes for the specification and maturation of STN neurons are still being debated. Moreover, most developmental studies have been carried out on animal models, but the results cannot be simply extrapolated to human brain. To gain a better understanding of processes involved in the development of human STN, we analyzed the expression of several transcription factors in the fetal STN during midgestation (15-20 post-conceptional weeks, PCW). Human fetal tissue was formalin-fixed, processed for paraffin-embedding, and cut at 10 µm. The expression of transcription factors (i.e. Foxp2, Foxp1, Foxa1, Barhl1, Pax6…) was studied using standard immunohistochemical methods. To the best of our knowledge, this is the first description of these transcription factors in the developing human STN. Our preliminary data indicate these trancription factors are important determinants of neuronal identity in the developing human STN and further studies considering their spatio-temporal expression throughout the embryonic and fetal period are needed.

The subthalamic nucleus (STN) is a small, lens- shaped structure providing the only glutamatergic input to the basal ganglia circuits. Like other basal ganglia structures, the nucleus is conventionally divided in three functional parts: motor, associative, and limbic territory. This subdivision is particularly useful for planning neurosurgical procedures like deep brain stimulation in which electrodes are implanted in the motor portion of the nucleus. However, the number of STN subdivisions reported in literature varies from 0 to 4 and the intricacies of its cellular composition are not well understood [1, 2] . In order to further explore STN neuronal populations, we performed immunohistochemical analysis of several well-known neuronal markers (NeuN, parvalbumin, calretinin, calbindin, nNOS) and transcription factors implicated in specifying neuronal phenotype (FOXP2, PAX6, NKX2.1) on post mortem adult human STN [3]. Using Stereo Investigator software, we estimated neuronal density, counted the number of immunoreactive neurons for each marker, and described their spatial distribution. The coordinates of neurons and contours of each STN were extracted to enable the final visualization of data using custom Python scripts. Generally, the analysed markers can be divided into two categories: one with density greater than 3000 neurons/mm3 (nNOS, PAX6, Nissl, FOXP2) and second with density around 2.200 neurons/mm3 (NeuN, NKX2.1, parvalbumin, calretinin). We didn’t observe clearly delineated zones of expression for each marker, but we detected a gradual increase of neuronal density from dorsolateral to ventromedial tip of the nucleus.

U poglavlju je dan pregled temeljnih spoznaja povezanih s razumijevanjem nastanka primarnih glavobolja: od otkrića Raya i Wolffa iz 1940. godine da je stupanj izazvane boli podraživanjem neke intrakranijske strukture upravno proporcionalan stupnju inervacije te strukture slobodnim živčanim završetcima perifernih nastavaka pseudounipolarnih neurona trigeminalnog ganglija (ganglion trigeminale seu semilunare Gasseri) i posljedičnoj aktivaciji drugog neurona uključenog u prijenos nociceptivnih signala koji se nalazi u spinalnoj trigeminalnoj jezgri (nucleus tractus spinalis nervi trigemini) odnosno tractus trigeminocervicalis (spinalna trigeminalna jezgra + neuroni koji se na nju u topografskom smislu nastavljaju prema kaudalno, a nalaze se u Rexedovom sloju I (lamina marginalis) stražnjeg roga leđne moždine cervikalnih segmenata C1, C2, katkad i C3), preko neurovaskularne teorije migrene Michaela Moskowitza (1979) i Petera Goadsbyja (1983), pa sve do suvremenih shvaćanja migrene kao neuropatske boli. Naime, budući da senzitizaciji trigeminalnih nociceptora i aktivaciji neurona trigeminocervikalnog kompleksa prethodi aktivnost pojedinih jezgara moždanog debla i šireća kortikalna depresija, migrena se posljednjih desetak godina više ne smatra vaskularnom, već neurogenom bolešću sa sekundarnim promjenama u perfuziji mozga. Karakteriziraju je ponavljajući napadaji glavobolje koji su uobičajeno popraćeni pridruženim simptomima mučnine i osjetne preosjetljivosti na svjetlo, zvuk i pokrete glave. Prepoznavanje ključne uloge kalcitoninu sličnog neuropeptida (calcitonin gene- related peptide, CGRP) i hipofiznog polipeptida koji aktivira adenilat ciklazu (pituitary adenylate cyclase-activating polypeptide, PACAP) u patofiziologiji migrene dovelo je do stvaranja novih i učinkovitih lijekova, od kojih su se monoklonska protutijela na CGRP receptor (erenumab) pokazala učinkovitima i u profilaksi.

The subthalamic nucleus (STN) is a small, biconvex nucleus in the diencephalon, lying rostrally from the internal capsule to substantia nigra caudally. To this day, two theories have been postulated about the developmental origin of the STN. One theory proposes that the STN originates from the separate longitudinal subthalamic zone between the ventral thalamus and the hypothalamus, while the other suggests that the nucleus originates from the germinative zone lying caudally from the mammillary recess. Novel studies investigating the development of mesencephalic dopaminergic (mesDA) neurons suggested, based on the expression profile of several transcriptional factors, that STN and mesDA neurons may have common neuronal lineage. However, the results of these studies are inconsistent and sometimes conflicting. Furthermore, majority of published studies were conducted using mouse brain, therefore leaving the question of possible interspecies differences unanswered. To further explore these developmental theories, we employed immunohistochemical staining to study the expression of several transcription factors (Foxp1, Foxp2, Foxa1, Barhl1, Dbx1, Nkx2.1) in the STN and SN of adult mouse, rat, and human. Data from our preliminary study indicate that some STN and SN neuronal populations have a common neuronal lineage, although some of the aforementioned transcription factors are expressed exclusively in the STN. These transcription factors could help us unravel the mystery of the STN development

Introduction: Advanced Parkinson’s disease patients with motor fluctuations that can no longer be controlled with medications are candidates for deep brain stimulation (DBS). Conflicting data about multimodal evoked potential changes, and cerebral vasomotor reactivity in those patients before and after DBS were described in literature. Aims: To determine the changes in latencies and amplitudes of visual, brainstem auditory, and somatosensory evoked potentials in advanced PD patients in comparison with healthy controls, and to correlate them with the changes in cerebral vasomotor reactivity, as well as to brainstem nuclei alterations. Methods: Measurements of latencies and amplitudes of visual, brainstem auditory and somatosensory evoked potentials (especially frontal N30 marker) were done in 10 advanced PD patients (HY 2-4), and compared to the results of the same measurements in 10 healthy controls matched for age and sex. Subsequently, transcranial Doppler was used to measure cerebral vasomotor reactivity, as well as for the detection of brainstem nuclei changes. The results were correlated to patient motor UPDRS scores. Results and conclusion: The preliminary results of this study demonstrated that significant differences in evoked potentials between PD patients and normal controls were observed. Furthermore, we were able to constantly correlate changes in evoked potentials with cerebral vasomotor reactivity as well as with changes in brainstem nuclei. Based on our findings, we hypothesize that this could potentially be a good marker for the evaluation of the successfulness of deep brain stimulation in PD patients. This work was supported by Croatian Science Foundation Start-Up grant awarded to G.S.

Peter Fonagy definirao je mentalizaciju kao proces kojime zaključujemo o akcijama i mentalnim stanjima (osjećajima, mislima, vjerovanjima i željama) koja ih motiviraju. Mentalizaciju koristimo u svakodnevnom životu kada razgovaramo s drugima i nastojimo vidjeti svijet iz njihove perspektive. Postoji nekoliko konceptualnih preklapanja s teorijom mentalizacije, od kojih su najznačajnije empatija i teorija uma. Teorija uma naziv je za sposobnost koju djeca stječu u dobi od 4-6 godina kada razumiju zadatke „lažnog vjerovanja”. Fonagyjev koncept mentalizacije ima temelje u razvojnoj psihologiji i teoriji privrženosti, a nove neuroznanstvene slikovne metode snažno podupiru taj koncept. Sigurna, privržena veza majke i djeteta koju potiču dopaminski i oksitocinski neuralni sustavi olakšava razvoj sposobnosti mentalizacije. Taj razvoj može biti narušen zanemarivanjem ili zlostavljanjem, što je često vidljivo kod oboljelih od graničnog poremećaja ličnosti. Ova teorijska znanja omogućila su razvoj nove, učinkovite terapije za granični poremećaj ličnosti. Terapija temeljena na mentalizaciji (MBT) zahtijeva angažiranog, empatičnog terapeuta koji će spremno objasniti mentalna stanja u terapeutskom odnosu. Poput kognitivno-bihevioralnih terapija, MBT traje kraće od psihodinamskih terapija i usredotočuje se na promatranje vlastitog ponašanja i razmišljanje o mentalnim stanjima koja su ga potaknula. Ovakva terapija nudi svojim klijentima dobro strukturiranu, sigurnu bazu unutar koje mogu naučiti regulirati svoje nestabilne afekte i ostvariti uspješne interpersonalne veze. MBT je randomiziranim kliničkim ispitivanjima potvrdila svoju uspješnost u liječenju graničnog poremećaja ličnosti, poremećaja hranjenja, obiteljskoj terapiji i tretmanima usmjerenim smanjenju školskog nasilja. Izneseni podaci pokazuju da bi MBT mogla biti uspješna i pristupačna terapija za različite psihičke bolesti., Peter Fonagy defined mentalisation as a process of making inferences about one’s own actions and the mental states (feelings, thoughts, beliefs and desires) behind them. We use mentalisation in our everyday communication when engaging in a conversation with another person. Several concepts overlap with the concept of mentalisation, with empathy and theory of mind being the most notable. Theory of mind refers to the ability which children fully develop at the age of 4-6 when they understand ‘false belief’ tasks. Fonagy’s concept of mentalisation has its origins in developmental psychology and attachment theory, with strong support from the newest neuroimaging studies. A safe, secure attachment relationship between mother and child, facilitated by dopaminergic and oxytocinergic neural circuits, fosters the development of the ability to mentalise. This development can be disrupted by early neglect or abuse, as often seen in patients with borderline personality disorder (BPD). Based upon this theoretical knowledge, a chance of developing a new, effective treatment for borderline personality disorder emerged. Mentalisation-based treatment (MBT) requires a more open-minded, empathic, and engaged therapist who willingly explains mental states in current therapeutic relationship. Similar to cognitive-behavioural therapies, MBT lasts shorter than psychoanalytic therapy, and places emphasis on observing one’s own behaviour and thinking about mental states which motivate that particular behaviour. This treatment offers its clients a well-structured, secure base within which they can learn to regulate their somewhat unstable emotions, and accomplish successful interpersonal relationships. MBT has proven its effectiveness in treatment of BPD in randomized-controlled trials, with successful application in family treatment, eating disorders, and school-based treatments for minimizing violence. The presented evidence shows that one should consider MBT as a new, successful, and accessible treatment for various psychiatric disorders.

Hormoni su signalne molekule koje se direktno izlučuju iz posebnih žlijezda, odnosno endokrinoloških tkiva u krv. Endokrinološki sustav zajedno s neurološkim čini osnovu po kojoj se zadržava homeostaza, tj. dinamička ravnoteža u organizmu. U hormone po kemijskoj strukturi ubrajamo nekoliko skupina spojeva: amine, polipeptide, proteine, glikoproteine i steroide. Hormoni mogu djelovati endokrino, preko lučenja spoja u krv i distribucije po organizmu, ali i parakrino tako da djeluje na stanice u svojoj blizini, kao i autokrino, tako da djeluje na samu stanicu što luči spoj. Hormonska regulacija tijesno je vezana uz središnji živčani sustav, ali i visceralne organe i periferna tkiva. Regulacija pojedinog hormona najčešće je uspostavljena hijerarhijski. U toj hijerarhiji, najviši centar je predstavljen dijelom međumozga, hipotalamusom koji upravlja radom hipofize, druge karike u lancu te na kraju slijedi ciljni endokrinološki organ koji luči hormon. Komunikacija među ovim strukturama se vrši neposredno preko razine konačnog produkta, tj. samog završnog hormona koji se luči, ali i posredno preko sastava tjelesnih tekućina i neuralnih signala. Postoje dvije varijante neposredne kontrole lučenja - pozitivna povratna sprega i negativna povratna sprega. Mehanizmom pozitivne povratne sprege povećava se otklon regulirane vrijednosti (hormona), dok se mehanizmom negativne povratne sprege otklon regulirane vrijednosti smanjuje. U slučaju fiziološke narušenosti i prisutnosti patološkog stanja, mehanizam povratne sprege može biti očuvan ili narušen. Mjerenjem razine pojedinog hormona u komunikacijskom lancu hipotalamus-hipofiza-ciljni organ može se utvrditi razina poremećaja. Hipotalamus luči hormone za poticanje ili kočenje lučenja hormona iz hipofize te se oni nazivaju liberini. Hipofiza je žlijezda koja se sastoji od embriološki različitih tkiva, pa ju prema tome možemo podijeliti na prednji dio ili adenohipofizu i stražnji dio ili neurohipofizu i koja je direktni nastavak moždanog tkiva. Adenohipofiza luči brojne hormone kao što su: ACTH, TSH, FSH, LH, GH i prolaktin dok neurohipofiza luči oksitocin i vazopresin. Portalni hipofizarni krvotok služi za brzu komunikaciju između hipotalamusa i hipofize. Primarno endokrinološki organi kao što su: hipofiza, epifiza, spolne žlijezde, štitna žlijezda, doštitne žlijezde, nadbubrežne žlijezde, masno tkivo i probavni sustav, u regulaciji homeostaze nadopunjavaju i sekundarni endokrinološki organi kao što su srce, bubreg, jetra i kost. Hormonski sustav može se podijeliti u nekoliko vitalnih osovina, a koje u slučaju poremetnje završavaju klinički jasnim simptomima i znakovima, tjelesnim promjenama i krajnjim centralnim učinkom na ponašanje. Osovinu rasta čine hipotalamički GHRH, somatostatin, hormon rasta i IGF-1. Osovinu štitnjače čine tireotropin, TSH te tiroksin i trijodtironin. Osovinu spol nih žlijezda čine hipotalamički GnRH, LH, FSH, estrogeni, progesteron, testosteron, inhibin i aktivin. Prolaktinsku osovinu čine dopamin i prolaktin. Osovinu nadbubrežne žlijezde čine hipotalamički CRH, ACTH i kortizol. Sama endokrinološka regulacija je mnogo složenija i postoje brojne interakcije i povezanost među pojedinima hormonima iz različitih osovina te bi njihovo izolirano promatranje predstavljalo značajan propust. Međutim, pojedini hormoni imaju određene specifičnosti te se takvim analitičkim pristupom može jasnije pristupiti problematici regulacije pojedine endokrine žlijezde. Osim hormona osovina ad- enohipofize koji su u centru razmatranja klasične endokrinologije, predstavljena su i saznanja o ulozi vazopresina i oksitocina, pogotovo ovog drugog za kojeg se utvrdila značajna uloga za ostvarivanje socijalnih kontakata. Novija istraživanja proširila su spektar proučavanja na još više hormona kao što su leptin, grelin i C-peptid, koji su važni prije svega za regulaciju energi- jskog statusa preko središnjeg živčanog sustava, ali i perifernih tkiva. Melatonin, hormon koji luči epifiza, sudjeluje u vrlo zanimljivom području ljudskog ponašanja: ritmu budnost-spavanje, koji je često narušen u somatskim ili psihičkim bolestima. Ovim pregledom nastojalo se pokriti osnovu razinu endokrinologije i interakcije središnjeg živčanog sustava sa perifernim tkivima prema trenutno dostupnim spoznajama.

Infografika nagrada i počasti znanstvenika Hrvatskog instituta za istraživanje mozga