Nucleus incertus ablation disrupted conspecific recognition and modified immediate early gene expression patterns in 'social brain' circuits of rats.

Social interaction involves neural activity in prefrontal cortex, septum, hippocampus, amygdala and hypothalamus. Notably, these areas all receive projections from the nucleus incertus (NI) in the pontine tegmentum. Therefore, we investigated the effect of excitotoxic lesions of NI neurons in adult male, Wistar rats on performance in a social discrimination test, and associated changes in immediate-early gene protein levels. NI was lesioned with quinolinic acid, and after recovery, rats underwent two trials in the 3-chamber test. In the first trial, NI-lesioned and sham-lesioned rats spent longer exploring a conspecific than an inanimate object. By contrast, in the second trial, NI-lesioned rats visited the familiar and novel conspecific chambers equally, whereas sham-lesioned rats spent longer engaging with the novel rat. Quantification of Fos- and Egr-1-immunoreactivity (IR) levels in brain areas implicated in social behaviour, revealed that social encounter and NI lesion produced complex, differential changes. For example, Egr-1-IR was broadly decreased in several amygdala nuclei in NI-lesioned rats relative to sham, but Fos-IR levels were unaltered. In hippocampus, NI-lesioned rats displayed decreased Fos-IR in CA2 and CA3, while Egr-1-IR was increased in the polymorphic dentate gyrus, CA1, CA2 and subiculum of NI-lesioned rats, relative to sham. Social encounter-related Egr-1-IR was also decreased in septum and anterior and lateral hypothalamus of NI-lesioned rats. Overall, these data suggest NI networks can modulate the activity of sensory, emotional and executive brain areas involved in social recognition, with a likely involvement of neuronal Egr-1 activation in amygdala, septum and hypothalamus, and Erg-1 inhibition in hippocampus.

[A new agent in the mechanisms underlying addiction and ingestion of alcohol: the nucleus incertus and the neuropeptide relaxin-3]. / Un nuevo agente en los mecanismos de la adiccion al alcohol y la ingesta: el nucleo incertus y el neuropeptido relaxina-3.

Alcohol intake is facilitated by its relationship with eating behavior and both processes are highly influenced by situations of stress and anxiety. The dysregulation of these processes can reach pathological situations such as anorexia, bulimia or obesity. The neurobiological elements which underlie this control are not completely clarified. The nucleus incertus (NI) in the pontine tegmentum is a common element in the food intake and alcoholism. NI is characterized by using the neuropeptide relaxin-3 (RLN3) as transmitter and its receptor RXFP3. In the present review, we will analyze the participation of the NI-RLN3-RXFP3 system in these behaviors under conditions of anxiety or stress in animal models. The activation of NI has a positive effect on intake (orexigenic) and generates a wide response in the amygdala modulating anxiety states. The activity of RLN3-RXFP3 in the amygdala could affect alcohol addiction since the application of the RXFP3 antagonist in extended amygdala attenuates the relapse to alcohol induced by stress. The neuroanatomical data indicate that the NI-RLN3-RXFP3 system acts on the feeding behavior and alcohol intake by means of projections parallel to the canonical mesolimbic pathways. Thus, data in animal models indicate that the NI-RLN3-RXFP3 system should be taken into account as a target in the future treatment of disorders of eating and alcohol addictive behaviors.

TITLE: Un nuevo agente en los mecanismos de la adiccion al alcohol y la ingesta: el nucleo incertus y el neuropeptido relaxina-3.La ingesta de alcohol esta facilitada por la relacion con la conducta alimentaria, y ambas conductas estan altamente influidas por situaciones de estres y ansiedad. La desregulacion de estos procesos puede llegar a situaciones patologicas, como la anorexia, la bulimia o la obesidad. Los elementos neurobiologicos que subyacen a este control no estan completamente esclarecidos. El nucleo incertus (NI) en el tegmento pontino constituye un elemento comun a la ingesta y a la adiccion al alcohol. Las neuronas del NI utilizan como señalizacion el neuropeptido relaxina-3 (RLN3) y su receptor RXFP3. En esta revision se analiza la participacion del sistema NI-RLN3-RXFP3 en estas conductas bajo condiciones de ansiedad o estres en modelos animales. La activacion del NI tiene un efecto positivo sobre la ingesta (orexigeno) y desarrolla una respuesta amplia en la amigdala, donde se modulan los estados de ansiedad. La actividad de RLN3-RXFP3 en la amigdala podria afectar a la adiccion al alcohol, ya que la aplicacion del antagonista de RXFP3 en la amigdala extendida atenua la recaida al alcohol inducida por el estres. Los datos neuroanatomicos indican que el sistema NI-RLN3-RXFP3 actua sobre la conducta de ingesta y adiccion al alcohol mediante proyecciones paralelas a las vias canonicas mesolimbicas. Con ello, los datos en modelos animales indican que el sistema NI-RLN3-RXFP3 deberia tenerse en cuenta como diana en el tratamiento futuro de trastornos de las conductas alimentarias y adictivas.

Electrolytic lesion of the nucleus incertus retards extinction of auditory conditioned fear.

Fear memory circuits in the brain function to allow animals and humans to recognize putative sources of danger and adopt an appropriate behavioral response; and research on animal models of fear have helped reveal the anatomical and neurochemical nature of these circuits. The nucleus (n.) incertus in the dorsal pontine tegmentum provides a strong GABAergic projection to forebrain 'fear centers' and is strongly activated by neurogenic stressors. In this study in adult male rats, we examined the effect of electrolytic lesions of n. incertus on different stages of the fear conditioning-extinction process and correlated the outcomes with anatomical data on the distribution of n. incertus-derived nerve fibers in areas implicated in fear circuits. In a contextual auditory fear conditioning paradigm, we compared freezing behavior in control (naïve) rats (n=23) and rats with sham- or electrolytic lesions of n. incertus (n=13/group). The effectiveness and extent of the lesions was assessed post-mortem using immunohistochemical markers for n. incertus neurons-calretinin and relaxin-3. There were no differences between the three experimental groups in the habituation, acquisition, or context conditioning phases; but n. incertus lesioned rats displayed a markedly slower, 'delayed' extinction of conditioned freezing responses compared to sham-lesion and control rats, but no differences in retrieval of extinguished fear. These and earlier findings suggest that n. incertus-related circuits normally promote extinction through inhibitory projections to the amygdala, which is involved in acquisition of extinction memories.