Ferrán Bertone, José Luis

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Ferrán Bertone, José Luis

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Anatomía Humana y Psicobiología

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Open Access
Sex‑dependent effects of forced exercise in the body composition of adolescent rats
(Nature Research, 2021-05-12) Kutsenko Shchegolska, Yevheniy; Barreda, A.; Toval Sánchez, José Ángel; Garrigos, D.; Martínez Morga, Marta; Ribeiro do Couto, Bruno; Ferrán Bertone, José Luis; Anatomía Humana y Psicobiología; Facultad de Medicina
Determining the body composition during adolescence can predict diseases such as obesity, diabetes, and metabolic syndromes later in life; and physical activity became an effective way to restore changes in body composition. However, current available literature assessing the body composition before, during and after adolescence in female and male rodents by in vivo techniques is scarce. Thus, by using computerized tomography, we aimed to define the baseline of the weight and body composition during the adolescence and young adulthood of female and male Sprague–Dawley rats (on P30, P60 and P90) under standard diet. Then, we determined the effect of 18 days of forced exercise on the body weight and composition during the early adolescence (P27-45). The highest percentual increments in weight, body volume and relative adipose contents occurred during the female and male adolescence. Forced running during the early adolescence decreased weight, body volume and relative adipose delta and increment values in males only. The adolescence of rats is a period of drastic body composition changes, where exercise interventions have sex-dependent effects. These results support a model that could open new research windows in the field of adolescent obesity.
Open Access
Multi-neuromeric origin of tyrosine hydroxylase-positive neurons within the substantia nigra and ventral tegmental area
(Frontiers Media, 2025-05-30) Ferrán Bertone, José Luis; Lucero-Arteaga, Franco; Ayad, Abdelmalik; Kutsenko Shchegolska, Yevheniy; Alonso Fuentes, Antonia; Ribeiro do Couto, Bruno; García-Cabezas, M.Á.; Tseng, Kuei Y.; Anatomía Humana y Psicobiología; Facultad de Medicina
During early developmental stages, the brain is divided into three primary regions: the forebrain (prosencephalon), the hindbrain (rhombencephalon), and the spinal cord. These regions are further segmented into transverse units called neuromeres, each with distinct molecular identities that guide their specialization through development. Such modular organization is evolutionarily conserved and shapes the structural and functional complexity of the brain. The substantia nigra (SN) and ventral tegmental area (VTA) are key midbrain regions involved in reward, motivation, and motor control. They contain dopamine-producing tyrosine hydroxylase (TH)-positive neurons, which are historically classified into three anatomical groups—A8 (retrorubral field), A9 (SN pars compacta), and A10 (VTA)—each with distinct anatomical and functional properties. Recent studies revealed further sub-regional organization along medial-lateral and anterior–posterior gradients, suggesting specialized roles tied to their developmental origins. This study uses the prosomeric framework to map the segmental distribution of TH-positive neurons within the SN and VTA across different mammalian species and developmental stages. Using a comparative analysis of rodent, non-human primate and human specimens, we were able to demonstrate that TH-positive neurons within the SN and VTA exhibit a multi-neuromeric organization, with neuronal populations distributed across the diencephalic prosomeres (dp1-dp3), the midbrain prosomeres (mp1-mp2) and the isthmic rhombomere (r0). It is therefore conceivable that such multi-neuromeric origin of TH-positive neurons within the SN and VTA likely influence the patterns of connectivity and functional specialization of the dopamine system.
Open Access
Prosomeric hypothalamic distribution of tyrosine hydroxylase positive cells in adolescent rats
(Frontiers Media, 2022-05-06) Bilbao, María G.; Garrigos, Daniel; Martínez Morga, Marta; Toval, Ángel; Kutsenko Shchegolska, Yevheniy; Bautista, Rosario; Barreda, Alberto; Ribeiro do Couto, Bruno; Puelles López, Luis; Ferrán Bertone, José Luis; Anatomía Humana y Psicobiología
Most of the studies on neurochemical mapping, connectivity, and physiology in the hypothalamic region were carried out in rats and under the columnar morphologic paradigm. According to the columnar model, the entire hypothalamic region lies ventrally within the diencephalon, which includes preoptic, anterior, tuberal, and mamillary anteroposterior regions, and sometimes identifying dorsal, intermediate, and ventral hypothalamic partitions. This model is weak in providing little or no experimentally corroborated causal explanation of such subdivisions. In contrast, the modern prosomeric model uses different axial assumptions based on the parallel courses of the brain floor, alar-basal boundary, and brain roof (all causally explained). This model also postulates that the hypothalamus and telencephalon jointly form the secondary prosencephalon, separately from and rostral to the diencephalon proper. The hypothalamus is divided into two neuromeric (transverse) parts called peduncular and terminal hypothalamus (PHy and THy). The classic anteroposterior (AP) divisions of the columnar hypothalamus are rather seen as dorsoventral subdivisions of the hypothalamic alar and basal plates. In this study, we offered a prosomeric immunohistochemical mapping in the rat of hypothalamic cells expressing tyrosine hydroxylase (TH), which is the enzyme that catalyzes the conversion of L-tyrosine to levodopa (L-DOPA) and a precursor of dopamine. This mapping was also combined with markers for diverse hypothalamic nuclei [agouti-related peptide (Agrp), arginine vasopressin (Avp), cocaine and amphetamine-regulated transcript (Cart), corticotropin releasing Hormone (Crh), melanin concentrating hormone (Mch), neuropeptide Y (Npy), oxytocin/neurophysin I (Oxt), proopiomelanocortin (Pomc), somatostatin (Sst), tyrosine hidroxilase (Th), and thyrotropin releasing hormone (Trh)]. TH-positive cells are particularly abundant within the periventricular stratum of the paraventricular and subparaventricular alar domains. In the tuberal region, most labeled cells are found in the acroterminal arcuate nucleus and in the terminal periventricular stratum. The dorsal retrotuberal region (PHy) contains the A13 cell group of TH-positive cells. In addition, some TH cells appear in the perimamillary and retromamillary regions. The prosomeric model proved useful for determining the precise location of TH-positive cells relative to possible origins of morphogenetic signals, thus aiding potential causal explanation of position-related specification of this hypothalamic cell type.
Restricted
Elucidating the neuromeric organization of the Mongolian gerbil brain
(Springer, 2025-11-04) Lucero-Arteaga, F.; Labegorra, S.; Abrego-Álvarez, A.; Heck, V.; Portu, A. I.; Boeris, M. A.; Alonso Fuentes, Antonia; Ribeiro do Couto, Bruno; García-Cabezas, M. Á.; Tseng, K. Y.; Ferrán Bertone, José Luis; Anatomía Humana y Psicobiología; Facultad de Medicina
The Mongolian Gerbil (Meriones unguiculatus) diverged from rats/mice around 45 million years ago and developed adaptations to extreme temperatures and water scarcity. Another feature of the Mongolian Gerbils is their social monogamy similar to that of prairie voles. These observations suggest that there are potential differences in the Mongolian Gerbil brain that are distinct from that of rats and mice. The goal of the present study is to establish the extent to which the neuromeric organization of the brain is conserved in the Mongolian Gerbil and to gain insights on how evolutionary expansion and diversification of brain regions occur across species. Our data shows that the multineuromeric origin of tyrosine hydroxylase-positive processes in the Mongolian Gerbil is similar to that in mice and rats, spanning from the diencephalon, midbrain, and the rostral hindbrain. There are also observable anatomical differences. However, most of the components characteristic of these neuromeres are identifiable in the Mongolian gerbil, closely mirroring those found in mice and rats. Together, these findings suggest that the conserved neuromeric organization likely stems from a restricted genetic toolset that began in the Muridae family 45 million years ago, and that a profound reorganization of the fundamental structural plan delineating the neuromeric segmentation is not required for the emergence of diverse functionality among species of phylogenetically related families. Future studies are needed to establish how the genetic programs within each neuromeric unit are influenced by environmental factors that ultimately impact the size of the neuromeric derivatives and their functional connectivity.
Open Access
TCF7L2 regulates postmitotic differentiation programmes and excitability patterns in the thalamus
(The company of Biologists Ltd., 2020-08-25) Andrzej Lipiec, Marcin; Bem, Joanna; Koziński, Kamil; Chakraborty, Chaitali; Urban-Ciećko, Joanna; Zajkowski, Tomasz; Dabrowski, Michał; Mateusz Szewczyk, Łukasz; Toval, Ángel; Ferrán Bertone, José Luis; Nagalsk, Andrzej; Wiśniewska, Marta Barbara; Anatomía Humana y Psicobiología; Facultad de Medicina
Neuronal phenotypes are controlled by terminal selector transcription factors in invertebrates, but only a few examples of such regulators have been provided in vertebrates. We hypothesised that TCF7L2 regulates different stages of postmitotic differentiation in the thalamus, and functions as a thalamic terminal selector. To investigate this hypothesis, we used complete and conditional knockouts of Tcf7l2 inmice. The connectivity and clustering of neurons were disrupted in the thalamo-habenular region in Tcf7l2−/− embryos. The expression of subregional thalamic and habenular transcription factors was lost and region-specific cell migration and axon guidance genes were downregulated. In mice with a postnatal Tcf7l2 knockout, the induction of genes that confer thalamic terminal electrophysiological features was impaired. Many of these genes proved to be direct targets of TCF7L2. The role of TCF7L2 in terminal selection was functionally confirmed by impaired firing modes in thalamic neurons in the mutantmice. These data corroborate the existence of master regulators in the vertebrate brain that control stage-specific genetic programmes and regional subroutines, maintain regional transcriptional network during embryonic development, and induce terminal selection postnatally.
Open Access
Habituation Training Improves Locomotor Performance in a Forced Running Wheel System in Rats
(Frontiers Media, 2017-03) Toval, Angel; Baños, Raúl; Morales-Delgado, Nicanor; Ayad, Abdelmalik; Tseng, Kuei Y.; Cruz Sánchez, Ernesto de la; García Pallarés, Jesús; Ferrán Bertone, José Luis; Anatomía Humana y Psicobiología
Increasing evidence supports that physical activity promotes mental health; and regular exercise may confer positive effects in neurological disorders. There is growing number of reports that requires the analysis of the impact of physical activity in animal models. Exercise in rodents can be performed under voluntary or forced conditions. The former presents the disadvantage that the volume and intensity of exercise varies from subject to subject. On the other hand, a major challenge of the forced training protocol is the low level of performance typically achieved within a given session. Thus, the aim of the present study was to evaluate the effectiveness of gradual increasing of the volume and intensity (training habituation protocol) to improve the locomotor performance in a forced running-wheel system in rats. Sprague-Dawley rats were randomly assigned to either a group that received an exercise training habituation protocol, or a control group. The locomotor performance during forced running was assessed by an incremental exercise test. The experimental results reveal that the total running time and the distance covered by habituated rats was significantly higher than in control ones. We conclude that the exercise habituation protocol improves the locomotor performance in forced running wheels.
Open Access
Atypical course of the habenulo-interpeduncular tract in chick embryos
(Wiley, 2024-07-30) Ferrán Bertone, José Luis; Puelles López, Luis; Anatomía Humana y Psicobiología; Facultad de Medicina
Classical studies of the avian diencephalon hardly mention the habenulo-interpeduncular tract (a.k.a. retroflex tract), although both the habenula (HB) (its origin) and the interpeduncular nuclear complex (its target) are present. Retroflex tract fibers were described at early embryonic stages but seem absent in the adult in routine stains. However, this tract is a salient diencephalic landmark in all other vertebrate lineages. It typically emerges out of the caudal HB, courses dorsoventrally across thalamic alar and basal plates just in front of the thalamo-pretectal boundary, and then sharply bends 90◦ caudalwards at paramedian basal plate levels (this is the “retroflexion”), to approach longitudinally via paramedian pretectum and midbrain the rostralmost hindbrain, specifically the prepontine median interpeduncular complex across isthmus and rhombomere 1. We systematize this habenulointerpeduncular course into four parts named subhabenular, retrothalamic, tegmental, and interpeduncular. We reexamined the chicken habenulo-interpeduncular fibers at stages HH30 and HH35 (6.5- and 9-day incubation) by mapping them specifically with immunoreaction for BEN protein, a well-known marker. We found that only a small fraction of the stained retroflex tract fibers approaches the basal plate by coursing along the standard dorsoventral pathway in front of the thalamo-pretectal boundary. Many other habenular fibers instead diverge into atypical dispersed courses across the thalamic cellmass (implying alteration of the first subhabenular part of the standard course) before reaching the basal plate; this dispersion explains their invisibility. A significant number of such transthalamic habenular fibers cross orthogonally the zona limitans (ZLI) (the rostral thalamic boundary) and invade the caudal alar prethalamus. Here, they immediately descend dorsoventrally, just rostrally to the ZLI, until reaching the prethalamic basal plate, where they bend (retroflex) caudalwards, entering the thalamic basal paramedian area. These atypical fibers gradually fasciculate with the other groups of habenular efferent fibers in their final longitudinal approach to the hindbrain interpeduncular complex.We conclude that the poor visibility of this tract in birds is due to its dispersion into a diversity of atypical alternative routes, though all components eventually reach the interpeduncular complex. This case merits further analysis of the diverse permissive versus nonpermissive guidance mechanisms called into action, which partially correlate distinctly with successive diencephalic, mesencephalic, and hindbrain neuromeric fields and their boundaries.
Open Access
Hypothalamic Crh/Avp, plasmatic glucose and lactate remain unchanged during habituation to forced exercise
(Frontiers, 2020-05-15) Toval, Angel; Vicente-Conesa, Francisco; Martinez-Ortega, Paloma; Kutsenko, Yevenhiy; Morales-Delgado, Nicanor; Garrigos, Daniel; Alonso Fuentes, Antonia; Ferrán Bertone, José Luis; Ribeiro do Couto, Bruno; Popovic Popovic, Miroljub; Anatomía Humana y Psicobiología
It has been demonstrated that physical activity contributes to a healthier life. However, there is a knowledge gap regarding the neural mechanisms producing these effects. One of the keystones to deal with this problem is to use training programs with equal loads of physical activity. However, irregular motor and stress responses have been found in murine exercise models. Habituation to forced exercise facilitates a complete response to a training program in all rodents, reaching the same load of physical activity among animals. Here, it was evaluated if glucose and lactate – which are stress biomarkers – are increased during the habituation to exercise. Sprague-Dawley rats received an 8-days habituation protocol with progressive increments of time and speed of running. Then, experimental and control (non-habituated) rats were subjected to an incremental test. Blood samples were obtained to determine plasmatic glucose and lactate levels before, immediately after and 30 min after each session of training. Crh and Avp mRNA expression was determined by two-step qPCR. Our results revealed that glucose and lactate levels are not increased during the habituation period and tend to decrease toward the end of the protocol. Also, Crh and Avp were not chronically activated by the habituation program. Lactate and glucose, determined after the incremental test, were higher in control rats without previous contact with the wheel, compared with habituated and wheel control rats. These results suggest that the implementation of an adaptive phase prior to forced exercise programs might avoid non-specific stress responses.
Open Access
Dopaminergic Modulation of Forced Running Performance in Adolescent Rats: Role of Striatal D1 and Extra-striatal D2 Dopamine Receptors
(Springer, 2021-01-04) Toval, Angel; Garrigos, Daniel; Kutsenko, Yevenhiy; Morales-Delgado, Nicanor; Tseng, Kuei I.; Ferrán Bertone, José Luis; Ribeiro do Couto, Bruno; Popovic Popovic, Miroljub; Anatomía Humana y Psicobiología
Improving exercise capacity during adolescence impacts positively on cognitive and motor functions. However, the neural mechanisms contributing to enhance physical performance during this sensitive period remain poorly understood. Such knowledge could help to optimize exercise programs and promote a healthy physical and cognitive development in youth athletes. The central dopamine system is of great interest because of its role in regulating motor behavior through the activation of D1 and D2 receptors. Thus, the aim of the present study is to determine whether D1 or D2 receptor signaling contributes to modulate the exercise capacity during adolescence and if this modulation takes place through the striatum. To test this, we used a rodent model of forced running wheel that we implemented recently to assess the exercise capacity. Briefly, rats were exposed to an 8-day period of habituation in the running wheel before assessing their locomotor performance in response to an incremental exercise test, in which the speed was gradually increased until exhaustion. We found that systemic administration of D1-like (SCH23390) and/or D2-like (raclopride) receptor antagonists prior to the incremental test reduced the duration of forced running in a dose-dependent manner. Similarly, locomotor activity in the open field was decreased by the dopamine antagonists. Interestingly, this was not the case following intrastriatal infusion of an effective dose of SCH23390, which decreased motor performance during the incremental test without disrupting the behavioral response in the open field. Surprisingly, intrastriatal delivery of raclopride failed to impact the duration of forced running. Altogether, these results indicate that the level of locomotor response to incremental loads of forced running in adolescent rats is dopamine dependent and mechanistically linked to the activation of striatal D1 and extra-striatal D2 receptors.
Open Access
Comunicaciones Orales.-Habituation training protocol improves exercise performance in a forced running wheel system in rats
(2020-05-26) Toval Sánchez, José A.; Baños, R.; Morales-Delgado, N.; Ayad, A.; Tseng, K. Y.; Cruz Sánchez, Ernesto de la; García Pallarés, Jesús; Puelles López, Luis; Ferrán Bertone, José Luis; Facultades, Departamentos, Servicios y Escuelas::Departamentos de la UMU::Anatomía Humana y Psicobiología; Facultades, Departamentos, Servicios y Escuelas::Facultades de la UMU::Facultad de Ciencias del Deporte