Contribution of the Roman rat lines/strains to personality neuroscience: neurobehavioral modeling of internalizing/externalizing psychopathologies

The Roman high-avoidance (RHA) and low-avoidance (RLA) rat lines/strains were established in Rome through bidirectional selection of Wistar rats for rapid (RHA) or extremely poor (RLA) acquisition of a two-way active avoidance task. Relative to RHAs, RLA rats exhibit enhanced threat sensitivity, anxiety, fear and vulnerability to stress, a passive coping style and increased sensitivity to frustration. Thus, RLA rats’ phenotypic profile falls well within the “internalizing” behavior spectrum. Compared with RLAs and other rat strains/stocks, RHAs present increased impulsivity and reward sensitivity, deficits in social behavior and attentional/cognitive processes, novelty-induced hyper-locomotion and vulnerability to psychostimulant sensitization and drug addiction. Thus, RHA rats’ phenotypes are consistent with a “disinhibiting externalizing” profile. Many neurobiological/molecular traits differentiate both rat lines/strains. For example, relative to RLA rats, RHAs exhibit decreased function of the prefrontal cortex (PFC), hippocampus and amygdala, increased functional tone of the mesolimbic dopamine system, a deficit of central metabotropic glutamate-2 (mGlu2) receptors, increased density of serotonin 5-HT2A receptors in the PFC, impairment of GABAergic transmission in the PFC, alterations of several synaptic markers and increased density of pyramidal immature dendrític spines in the PFC. These characteristics suggest an immature brain of RHA rats and are reminiscent of schizophrenia features like hypofrontality and disruption of the excitation/inhibition cortical balance. We review evidence supporting RLA rats as a valid model of anxiety/fear, stress and frustration vulnerability, whereas RHA rats represent a promising translational model of neurodevelopmental alterations related to impulsivity, schizophrenia-relevant features and comorbidity with drug addiction vulnerability

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Sintomatología negativa de la esquizofrenia en un modelo genético de ratas : validación conductual y farmacológica en las cepas de ratas Roman

La present Dissertació Doctoral concentra una sèrie d'estudis que afegeixen noves evidències conductuals, farmacològiques i neuroanatòmiques (d'activitat cel·lular) en suport de la validesa d'un model animal de trets rellevants per a l'esquizofrènia, la soca de rates 'Romanes de alta evitació' (RHA; comparades amb les 'Romanes de baixa evitació', o RLA). Al llarg de les darreres dècades, el nostre grup d'investigació s'ha centrat en aspectes del model relacionats amb la simptomatologia positiva i cognitiva de l'esquizofrènia, sense aprofundir en aspectes de la simptomatologia negativa. La recerca que aquí es presenta va destinada a investigar per primera vegada aspectes relacionats amb la simptomatologia negativa de la malaltia, com l'associalitat o manca d'interès per la conducta social. L'aspecte conductual simptomatològic comú entre els diferents estudis aquí presentats és l'associalitat, o retraïment social, un dels símptomes negatius més importants de l'esquizofrènia. Per tant, models animals capaços de modular diferents aspectes del desinterès per la interacció social poden ser valuosos per ampliar el coneixement sobre les característiques neurobiològiques subjacents a aquest aspecte de la simptomatologia negativa de l'esquizofrènia. En els primers estudis (Estudis 1-3), hem observat diferències entre les soques de rates Romanes (RHA vs. RLA) en relació amb la conducta social. Hem observat que la soca de rates RHA presenta una menor preferència social que la soca de rates RLA (Estudi 1), i que les femelles adultes de la soca RHA mostren una major preferència social que els mascles de la mateixa soca. A més a més, els resultats revelen una reducció en la preferència social dels animals adults en comparació amb els animals joves (Estudi 3). D'altre banda, hem estudiat els efectes del tractament ambiental d'estimulació neonatal (NH, de l'anglès 'neonatal handling') sobre la conducta social i sobre l'expressió de c-Fos (com a mesura d'activitat cel·lular) en diferents àrees cerebrals en ambdues soques (Estudi 1-2). El tractament NH ha estat capaç d'augmentar la interacció social en ambdues soques amb un efecte més marcat en la soca RHA, així com d'augmentar de forma específica l'expressió de c-Fos en zones de l'escorça prefrontal i subregions de l'amígdala de les rates RHA (Estudi 2). Per últim, i continuant amb la validació del model, en els estudis següents (Estudi 4-5) es va abordar l'objectiu general de la Dissertació Doctoral des d'una perspectiva farmacològica. Així, l'administració d'un antagonista del receptor glutamatèrgic NMDA, el MK801, vam veure que produeix un major dèficit de la conducta social i una major hiperactivitat en rates RHA que en les rates RLA (ambdós efectes considerats com a models d'aspectes relacionats amb l'esquizofrènia). D'altra banda, vam observar que l'administració de varis antipsicòtics atenua els efectes del MK801 sobre la preferència social i l'activitat locomotora, en major mesura en la soca RHA que en la soca RLA, essent l'antipsicòtic aripiprazol el que presenta major activitat 'terapèutica' (Estudi 4). De forma similar, l'administració concomitant de MK801 i oxitocina, un neuropèptid amb propietats antipsicòtiques naturals, va produir una atenuació dels efectes negatius del MK801 sobre la conducta social i la hiperactivat. Aquest efecte va resultar aparentment més marcat en la soca RHA que en la soca RLA (Estudi 5). Les dades que es mostren en aquesta Dissertació Doctoral afegeixen validesa aparent, de constructe i predictiva al model animal proposat, les rates RHA, com un recurs útil per la investigació i millor comprensió d'aspectes neurobiològics i conductuals rellevants per l'esquizofrènia.La presente Disertación Doctoral concentra una serie de estudios que añaden nuevas evidencias conductuales, farmacológicas y neuroanatómicas (de actividad celular cerebral) en apoyo de la validez de un modelo animal de rasgos relevantes para la esquizofrenia, la cepa de ratas 'Roman de alta evitación' (RHA; comparadas con las 'Roman de baja evitación', o RLA). A lo largo de las últimas décadas nuestro grupo de investigación se ha centrado en aspectos del modelo relacionados con la sintomatología positiva y cognitiva de la esquizofrenia, sin profundizar en aspectos de la sintomatología negativa. Los estudios que aquí se presentan van destinados a investigar por primera vez aspectos relacionados con la sintomatología negativa de la esquizofrenia, como la asociabilidad o falta de interés por la conducta social. El aspecto conductual sintomatológico común entre los distintos estudios aquí presentados es la asociabilidad. En la esquizofrenia, la asociabilidad o retraimiento social, es uno de los síntomas negativos más importantes, y puede entenderse como una reducción en la motivación para crear nuevas relaciones con los demás. Por lo tanto, modelos animales capaces de modular diferentes aspectos del desinterés por la interacción social pueden ser valiosos para ampliar el conocimiento sobre las características neurobiológicas subyacentes a este aspecto de la sintomatología negativa de la esquizofrenia. En los primeros estudios (Estudios 1-3) hemos observado diferencias entre las cepas de ratas Roman (RHA vs. RLA) en relación con la conducta social. Hemos observado que la cepa de ratas RHA presenta una menor preferencia social que la cepa de ratas RLA (Estudio 1). Además, los resultados revelan una reducción en preferencia social de los animales adultos en comparación con los animales jóvenes, así como que las hembras adultas de la cepa RHA muestran una mayor preferencia social que los machos de la misma cepa (Estudio 3). Del mismo modo, hemos estudiado los efectos del tratamiento ambiental de estimulación neonatal (NH, del inglés 'neonatal handling') sobre la conducta social y sobre la expresión de c-Fos (como medida de activación celular) en varias áreas cerebrales en ambas cepas (Estudio 2). El tratamiento de NH ha sido capaz de aumentar la interacción social en ambas cepas con un efecto más marcado en las ratas RHA, así como de aumentar de forma específica la expresión de c-Fos en zonas de la corteza prefrontal y subregiones de la amígdala de las ratas RHA (Estudio 2). Por último, y continuando con la validación del modelo, en los estudios siguientes (Estudio 4-5) se abordó el objetivo general de la Disertación Doctoral desde una perspectiva farmacológica. Así, la administración de un antagonista del receptor glutamatérgico NMDA, el MK801, produce un mayor déficit de conducta social y una mayor hiperactividad (ambos efectos considerados como modelos de aspectos relacionados con la esquizofrenia) en las ratas RHA que en las ratas RLA. Así mismo, la administración de varios antipsicóticos atípicos atenúa los efectos del MK801 sobre la preferencia social y la actividad locomotora en mayor medida en la cepa RHA que en la cepa RLA, siendo el antipsicótico aripiprazol el que presenta mayor actividad 'terapéutica' (Estudio 4). De modo similar, la administración concomitante de MK801 y oxitocina, un neuropéptido con propiedades antipsicóticas naturales, produjo una atenuación de los efectos negativos del MK801 sobre la conducta social y la hiperactividad. Dicho efecto resultó aparentemente más marcado en la cepa RHA que en la cepa RLA (Estudio 5). Los datos que se muestran en esta Disertación Doctoral añaden validez aparente, de constructo y predictiva al modelo animal propuesto, las ratas RHA, como un recurso útil para la investigación y mejor comprensión de aspectos neurobiológicos y conductuales relevantes para la esquizofrenia.This Doctoral Dissertation focuses on a series of studies that add new behavioural, pharmacological, and neuroanatomical evidence (of cell activity) in support of the validity of an animal model of schizophrenia-relevant traits, the 'Roman High Avoidance' strain of rats (RHA; compared to 'Roman Low Avoidance', or RLA). Along the last decades, our research group has focused on aspects of the model related to the positive and cognitive symptomatology of schizophrenia, without delving into aspects of negative symptomatology. The studies presented here intended to investigate, for the first time, aspects related to the negative symptomatology of schizophrenia, such as asociality or lack of interest in social behaviour. The common symptomatologic behavioural aspect among the different studies presented here is asociality. In schizophrenia, asociality or social withdrawal is one of the most important negative symptoms and it can be understood as a reduction in the motivation to create new relationships with others. Therefore, animal models recapitulating different aspects of lack of motivation for social interaction may be valuable to expand our knowledge about the neurobiological characteristics underlying this aspect of the negative symptomatology of schizophrenia. In the first studies (Studies 1-3) we observed differences between the Roman rat strains (RHA vs. RLA) in relation to social behaviour. We have observed that the RHA rat strain exhibits lower social preference than the RLA rat strain (Study 1). In addition, the results reveal a reduction in social preference of adult animals compared to young animals, as well as that adult females of the RHA strain show a greater social preference than males of the same strain (Study 3). Furthermore, we have studied the effects of neonatal handling (NH; a neonatal environmental stimulation treatment) on social behaviour and c-Fos expression (as a measure of neuronal activation) in various brain areas in both rat strains (Study 1-2). NH treatment was able to increase the social preference of both strains with a more marked effect in RHA rats, and the treatment specifically increased the expression of c-Fos in areas of the prefrontal cortex and subregions of the amygdala of RHA rats (Study 2). Finally, in the following studies (Study 4-5) the general objective of the Doctoral Dissertation was addressed from a pharmacological perspective. Thus, the administration of a glutamatergic NMDA receptor antagonist, MK801, produces greater deficits in social behaviour and greater hyperactivity (both effects are considered to model aspects related to schizophrenia) in RHA rats than RLA rats. Likewise, the administration of various atypical antipsychotics attenuates the effects of MK801 on social preference and locomotor activity to a greater extent in the RHA strain than in RLA rats, with the antipsychotic aripiprazole showing the greatest "therapeutic" activity (Study 4). Similarly, concomitant administration of MK801 and oxytocin, a neuropeptide with natural antipsychotic properties, resulted in attenuation of the negative effects of MK801 on social behaviour and hyperactivity. This effect was apparently more marked in the RHA strain than in RLA rats (Study 5). The data reported in this Doctoral Dissertation add face, construct, and predictive validity to the proposed animal model, the RHA rats, as a useful tool for research and for a better understanding of neurobiological and behavioural aspects relevant to schizophrenia

Sintomatología negativa de la esquizofrenia en un modelo genético de ratas: validación conductual y farmacológica en las cepas de ratas Roman

La present Dissertació Doctoral concentra una sèrie d’estudis que afegeixen noves evidències conductuals, farmacològiques i neuroanatòmiques (d’activitat cel·lular) en suport de la validesa d’un model animal de trets rellevants per a l’esquizofrènia, la soca de rates ‘Romanes de alta evitació’ (RHA; comparades amb les ‘Romanes de baixa evitació’, o RLA). Al llarg de les darreres dècades, el nostre grup d’investigació s’ha centrat en aspectes del model relacionats amb la simptomatologia positiva i cognitiva de l’esquizofrènia, sense aprofundir en aspectes de la simptomatologia negativa. La recerca que aquí es presenta va destinada a investigar per primera vegada aspectes relacionats amb la simptomatologia negativa de la malaltia, com l’associalitat o manca d’interès per la conducta social. L’aspecte conductual simptomatològic comú entre els diferents estudis aquí presentats és l’associalitat, o retraïment social, un dels símptomes negatius més importants de l’esquizofrènia. Per tant, models animals capaços de modular diferents aspectes del desinterès per la interacció social poden ser valuosos per ampliar el coneixement sobre les característiques neurobiològiques subjacents a aquest aspecte de la simptomatologia negativa de l’esquizofrènia. En els primers estudis (Estudis 1-3), hem observat diferències entre les soques de rates Romanes (RHA vs. RLA) en relació amb la conducta social. Hem observat que la soca de rates RHA presenta una menor preferència social que la soca de rates RLA (Estudi 1), i que les femelles adultes de la soca RHA mostren una major preferència social que els mascles de la mateixa soca. A més a més, els resultats revelen una reducció en la preferència social dels animals adults en comparació amb els animals joves (Estudi 3). D’altre banda, hem estudiat els efectes del tractament ambiental d’estimulació neonatal (NH, de l’anglès ‘neonatal handling’) sobre la conducta social i sobre l’expressió de c-Fos (com a mesura d’activitat cel·lular) en diferents àrees cerebrals en ambdues soques (Estudi 1-2). El tractament NH ha estat capaç d’augmentar la interacció social en ambdues soques amb un efecte més marcat en la soca RHA, així com d’augmentar de forma específica l’expressió de c-Fos en zones de l’escorça prefrontal i subregions de l’amígdala de les rates RHA (Estudi 2). Per últim, i continuant amb la validació del model, en els estudis següents (Estudi 4-5) es va abordar l’objectiu general de la Dissertació Doctoral des d’una perspectiva farmacològica. Així, l’administració d’un antagonista del receptor glutamatèrgic NMDA, el MK801, vam veure que produeix un major dèficit de la conducta social i una major hiperactivitat en rates RHA que en les rates RLA (ambdós efectes considerats com a models d’aspectes relacionats amb l’esquizofrènia). D’altra banda, vam observar que l’administració de varis antipsicòtics atenua els efectes del MK801 sobre la preferència social i l’activitat locomotora, en major mesura en la soca RHA que en la soca RLA, essent l’antipsicòtic aripiprazol el que presenta major activitat ‘terapèutica’ (Estudi 4). De forma similar, l’administració concomitant de MK801 i oxitocina, un neuropèptid amb propietats antipsicòtiques naturals, va produir una atenuació dels efectes negatius del MK801 sobre la conducta social i la hiperactivat. Aquest efecte va resultar aparentment més marcat en la soca RHA que en la soca RLA (Estudi 5). Les dades que es mostren en aquesta Dissertació Doctoral afegeixen validesa aparent, de constructe i predictiva al model animal proposat, les rates RHA, com un recurs útil per la investigació i millor comprensió d’aspectes neurobiològics i conductuals rellevants per l’esquizofrènia.La presente Disertación Doctoral concentra una serie de estudios que añaden nuevas evidencias conductuales, farmacológicas y neuroanatómicas (de actividad celular cerebral) en apoyo de la validez de un modelo animal de rasgos relevantes para la esquizofrenia, la cepa de ratas ‘Roman de alta evitación’ (RHA; comparadas con las ‘Roman de baja evitación’, o RLA). A lo largo de las últimas décadas nuestro grupo de investigación se ha centrado en aspectos del modelo relacionados con la sintomatología positiva y cognitiva de la esquizofrenia, sin profundizar en aspectos de la sintomatología negativa. Los estudios que aquí se presentan van destinados a investigar por primera vez aspectos relacionados con la sintomatología negativa de la esquizofrenia, como la asociabilidad o falta de interés por la conducta social. El aspecto conductual sintomatológico común entre los distintos estudios aquí presentados es la asociabilidad. En la esquizofrenia, la asociabilidad o retraimiento social, es uno de los síntomas negativos más importantes, y puede entenderse como una reducción en la motivación para crear nuevas relaciones con los demás. Por lo tanto, modelos animales capaces de modular diferentes aspectos del desinterés por la interacción social pueden ser valiosos para ampliar el conocimiento sobre las características neurobiológicas subyacentes a este aspecto de la sintomatología negativa de la esquizofrenia. En los primeros estudios (Estudios 1-3) hemos observado diferencias entre las cepas de ratas Roman (RHA vs. RLA) en relación con la conducta social. Hemos observado que la cepa de ratas RHA presenta una menor preferencia social que la cepa de ratas RLA (Estudio 1). Además, los resultados revelan una reducción en preferencia social de los animales adultos en comparación con los animales jóvenes, así como que las hembras adultas de la cepa RHA muestran una mayor preferencia social que los machos de la misma cepa (Estudio 3). Del mismo modo, hemos estudiado los efectos del tratamiento ambiental de estimulación neonatal (NH, del inglés ‘neonatal handling’) sobre la conducta social y sobre la expresión de c-Fos (como medida de activación celular) en varias áreas cerebrales en ambas cepas (Estudio 2). El tratamiento de NH ha sido capaz de aumentar la interacción social en ambas cepas con un efecto más marcado en las ratas RHA, así como de aumentar de forma específica la expresión de c-Fos en zonas de la corteza prefrontal y subregiones de la amígdala de las ratas RHA (Estudio 2). Por último, y continuando con la validación del modelo, en los estudios siguientes (Estudio 4-5) se abordó el objetivo general de la Disertación Doctoral desde una perspectiva farmacológica. Así, la administración de un antagonista del receptor glutamatérgico NMDA, el MK801, produce un mayor déficit de conducta social y una mayor hiperactividad (ambos efectos considerados como modelos de aspectos relacionados con la esquizofrenia) en las ratas RHA que en las ratas RLA. Así mismo, la administración de varios antipsicóticos atípicos atenúa los efectos del MK801 sobre la preferencia social y la actividad locomotora en mayor medida en la cepa RHA que en la cepa RLA, siendo el antipsicótico aripiprazol el que presenta mayor actividad ‘terapéutica’ (Estudio 4). De modo similar, la administración concomitante de MK801 y oxitocina, un neuropéptido con propiedades antipsicóticas naturales, produjo una atenuación de los efectos negativos del MK801 sobre la conducta social y la hiperactividad. Dicho efecto resultó aparentemente más marcado en la cepa RHA que en la cepa RLA (Estudio 5). Los datos que se muestran en esta Disertación Doctoral añaden validez aparente, de constructo y predictiva al modelo animal propuesto, las ratas RHA, como un recurso útil para la investigación y mejor comprensión de aspectos neurobiológicos y conductuales relevantes para la esquizofrenia.This Doctoral Dissertation focuses on a series of studies that add new behavioural, pharmacological, and neuroanatomical evidence (of cell activity) in support of the validity of an animal model of schizophrenia-relevant traits, the ‘Roman High Avoidance’ strain of rats (RHA; compared to ‘Roman Low Avoidance’, or RLA). Along the last decades, our research group has focused on aspects of the model related to the positive and cognitive symptomatology of schizophrenia, without delving into aspects of negative symptomatology. The studies presented here intended to investigate, for the first time, aspects related to the negative symptomatology of schizophrenia, such as asociality or lack of interest in social behaviour. The common symptomatologic behavioural aspect among the different studies presented here is asociality. In schizophrenia, asociality or social withdrawal is one of the most important negative symptoms and it can be understood as a reduction in the motivation to create new relationships with others. Therefore, animal models recapitulating different aspects of lack of motivation for social interaction may be valuable to expand our knowledge about the neurobiological characteristics underlying this aspect of the negative symptomatology of schizophrenia. In the first studies (Studies 1-3) we observed differences between the Roman rat strains (RHA vs. RLA) in relation to social behaviour. We have observed that the RHA rat strain exhibits lower social preference than the RLA rat strain (Study 1). In addition, the results reveal a reduction in social preference of adult animals compared to young animals, as well as that adult females of the RHA strain show a greater social preference than males of the same strain (Study 3). Furthermore, we have studied the effects of neonatal handling (NH; a neonatal environmental stimulation treatment) on social behaviour and c-Fos expression (as a measure of neuronal activation) in various brain areas in both rat strains (Study 1-2). NH treatment was able to increase the social preference of both strains with a more marked effect in RHA rats, and the treatment specifically increased the expression of c-Fos in areas of the prefrontal cortex and subregions of the amygdala of RHA rats (Study 2). Finally, in the following studies (Study 4-5) the general objective of the Doctoral Dissertation was addressed from a pharmacological perspective. Thus, the administration of a glutamatergic NMDA receptor antagonist, MK801, produces greater deficits in social behaviour and greater hyperactivity (both effects are considered to model aspects related to schizophrenia) in RHA rats than RLA rats. Likewise, the administration of various atypical antipsychotics attenuates the effects of MK801 on social preference and locomotor activity to a greater extent in the RHA strain than in RLA rats, with the antipsychotic aripiprazole showing the greatest “therapeutic” activity (Study 4). Similarly, concomitant administration of MK801 and oxytocin, a neuropeptide with natural antipsychotic properties, resulted in attenuation of the negative effects of MK801 on social behaviour and hyperactivity. This effect was apparently more marked in the RHA strain than in RLA rats (Study 5). The data reported in this Doctoral Dissertation add face, construct, and predictive validity to the proposed animal model, the RHA rats, as a useful tool for research and for a better understanding of neurobiological and behavioural aspects relevant to schizophrenia.Universitat Autònoma de Barcelona. Programa de Doctorat en Neurocièncie

Contribution of the Roman rat lines/strains to personality neuroscience : neurobehavioral modeling of internalizing/externalizing psychopathologies

Altres ajuts: acords transformatius de la UABThe Roman high-avoidance (RHA) and low-avoidance (RLA) rat lines/strains were established in Rome through bidirectional selection of Wistar rats for rapid (RHA) or extremely poor (RLA) acquisition of a two-way active avoidance task. Relative to RHAs, RLA rats exhibit enhanced threat sensitivity, anxiety, fear and vulnerability to stress, a passive coping style and increased sensitivity to frustration. Thus, RLA rats' phenotypic profile falls well within the "internalizing" behavior spectrum. Compared with RLAs and other rat strains/stocks, RHAs present increased impulsivity and reward sensitivity, deficits in social behavior and attentional/cognitive processes, novelty-induced hyper-locomotion and vulnerability to psychostimulant sensitization and drug addiction. Thus, RHA rats' phenotypes are consistent with a "disinhibiting externalizing" profile. Many neurobiological/molecular traits differentiate both rat lines/strains. For example, relative to RLA rats, RHAs exhibit decreased function of the prefrontal cortex (PFC), hippocampus and amygdala, increased functional tone of the mesolimbic dopamine system, a deficit of central metabotropic glutamate-2 (mGlu2) receptors, increased density of serotonin 5-HT2A receptors in the PFC, impairment of GABAergic transmission in the PFC, alterations of several synaptic markers and increased density of pyramidal immature dendrític spines in the PFC. These characteristics suggest an immature brain of RHA rats and are reminiscent of schizophrenia features like hypofrontality and disruption of the excitation/inhibition cortical balance. We review evidence supporting RLA rats as a valid model of anxiety/fear, stress and frustration vulnerability, whereas RHA rats represent a promising translational model of neurodevelopmental alterations related to impulsivity, schizophrenia-relevant features and comorbidity with drug addiction vulnerability

Decreased activation of parvalbumin interneurons in the medial prefrontal cortex in intact inbred Roman rats with schizophrenia-like reduced sensorimotor gating

Prepulse inhibition (PPI) allows assessing schizophrenia-like sensorimotor gating deficits in rodents. Previous studies indicate that PPI is modulated by the medial prefrontal cortex (mPFC), which is in agreement with our findings showing that PPI differences in the Roman rats are associated with divergences in mPFC activity. Here, we explore whether differences in PPI and mPFC activity in male Roman rats can be explained by (i) differences in the activation (c-Fos) of inhibitory neurons (parvalbumin (PV) interneurons); and/or (ii) reduced excitatory drive (PSD-95) to PV interneurons. Our data show that low PPI in the Roman high-avoidance (RHA) rats is associated with reduced activation of PV interneurons. Moreover, the RHA rats exhibit decreased density of both PV interneurons and PSD-95 puncta on active PV interneurons. These findings point to reduced cortical inhibition as a candidate to explain the schizophrenia-like features observed in RHA rats and support the role of impaired cortical inhibition in schizophrenia

Schizophrenia-like reduced sensorimotor gating in intact inbred and outbred rats is associated with decreased medial prefrontal cortex activity and volume

Prepulse inhibition (PPI) of startle response is a measure of sensorimotor gating that is impaired in schizophrenia and in many other clinical conditions. Rat models using pharmacological or surgical strategies reveal that PPI is modulated by the cortico-striatal-pallido-thalamic (CSPT) circuit. Here, we explore whether spontaneous variation in PPI in intact inbred and outbred rats is associated with functional and structural differences in the CSPT circuit. Inbred Roman High-(RHA) and Low-avoidance (RLA) and outbred heterogeneous stock (HS) rats were assessed for PPI, brain activity, and brain volume. Brain activity was assessed by c-Fos expression and brain volume by magnetic resonance imaging. Relevant structures of the CSPT circuit were evaluated, such as the medial prefrontal cortex (mPFC), cingulate cortex, hippocampus (HPC), amygdala, nucleus accumbens (NAc), and dorsal striatum. RHA showed lower PPI than RLA rats, while HS rats were stratified by their PPI levels in three groups. Reduced PPI was accompanied by decreased mPFC activity in Roman and HS rats and increased NAc shell activity in HS rats. Low PPI was also associated with decreased mPFC and HPC volumes in Roman and HS rats. This study reports a consistent relationship between decreased function and volume of the mPFC and spontaneous low-PPI levels in inbred and outbred intact rats. Moreover, our findings suggest that, apart from a hypoactive and smaller mPFC, a hyperactive NAc and smaller HPC may underlie reduced PPI levels. Our results support the notion that sensorimotor gating is modulated by forebrain structures and highlight the importance of the mPFC in its regulation

Increased exploratory activity in rats with deficient sensorimotor gating: a study of schizophrenia-relevant symptoms with genetically heterogeneous NIH-HS and Roman rat strains

Schizophrenia involves positive, negative and cognitive symptoms, as well as comorbidity with anxiety and obsessive-compulsive disorder. Prepulse inhibition (PPI) of the startle response is a measure of sensorimotor gating that is impaired in schizophrenia and animal models of the disease. Remarkably, impaired PPI has been related to other schizophrenia-like features in rodent models, such as cognitive deficits and hyperactivity. However, it remains to be investigated whether deficient PPI and increased exploratory activity are associated in genetically heterogeneous (outbred) naïve animals. This study was undertaken to evaluate the relationships among PPI and other schizophrenia-related symptoms, such as augmented exploratory activity, anxiety and compulsivity in the genetically heterogeneous (outbred) NIH-HS rat stock (HS) and in the genetically-selected inbred Roman High-Avoidance (RHA) and Low-avoidance (RLA) rats. Animals underwent the following tests: open-field (exploratory activity), elevated zero-maze (anxiety-like behavior), marble burying (compulsive-like behavior), and PPI. Three groups of HS rats were formed according to their PPI scores, i.e. Low-PPI, Medium-PPI and High-PPI. The HS Low-PPI group displayed higher exploratory activity in the open-field than the HS Medium-PPI and HS High-PPI groups. Likewise, compared with their RLA counterparts, RHA rats exhibited lower PPI and more intense exploratory activity in the open-field test. Correlational and factorial analyses of the whole HS sample and the RHA/RLA data globally corroborated the results of the PPI-stratified HS subgroups. These data suggest that such a consistent association between impaired PPI and increased exploratory activity in outbred HS and inbred RHA/RLA rats is a relevant parameter that must be taken into account when modeling clusters of schizophrenia-relevant symptoms

Oxytocin attenuates schizophrenia-like reduced sensorimotor gating in outbred and inbred rats in line with strain differences in CD38 gene expression

Prepulse inhibition (PPI) of the startle response is a measure of sensorimotor gating that is impaired in many clinical conditions, including schizophrenia. The inbred Roman high-avoidance (RHA) rats, compared to their low-avoidance (RLA) counterparts, show distinct schizophrenia-like phenotypes, such as spontaneous deficits in PPI accompanied by decreased medial prefrontal cortex (mPFC) activity and volume. Schizophrenia-like deficits are usually attenuated by antipsychotic drugs, but these drugs often produce severe side effects. In order to reduce these side effects, the neuropeptide oxytocin has been proposed as an alternative natural antipsychotic for schizophrenia. Here, we examined the effects of peripheral oxytocin administration (saline, 0.04, and 0.2 mg/kg) on PPI in the RHA vs. RLA rats, as well as in the outbred heterogeneous stock (HS) rats. Our results showed that oxytocin increased PPI in the HS rats and attenuated PPI deficits in the RHA rats, but it did not significantly affect PPI in the RLAs. To explore whether these divergent effects were associated with differences in oxytocinergic mechanisms, we analyzed gene expression of the oxytocin receptor (OXTR) and the regulator of oxytocin release (CD38) in the mPFC of the Roman rats. Consistent with the differential oxytocin effects on PPI (RHA > RLA), constitutive CD38 expression was reduced in the RHA rats compared to the RLAs, while oxytocin administration increased OXTR expression in both strains. Overall, the present work reveals that oxytocin administration shows antipsychotic-like effects on PPI in outbred and inbred rats, and it suggests that these effects may be related to basal differences in oxytocin-mediated mechanisms in the mPFC