Becoming stressed: Does the age matter? Reviewing the neurobiological and socio-affective effects of stress throughout the lifespan

Social and affective relations occur at every stage of our lives. Impairments in the quality of this “social world” can be exceptionally detrimental and lead to psychopathology or pathological behavior, including schizophrenia, autism spectrum disorder, affective disorders, social phobia or violence, among other things. Exposure to highly stressful or traumatic events, depending on the stage of life in which stress exposure occurs, could severely affect limbic structures, including the amygdala, and lead to alterations in social and affective behaviors. This review summarizes recent findings from stress research and provides an overview of its age-dependent effects on the structure and function of the amygdala, which includes molecular and cellular changes, and how they can trigger deviant social and affective behaviors. It is important to highlight that discoveries in this field may represent a breakthrough both for medical science and for society, as they may help in the development of new therapeutic approaches and prevention strategies in neuropsychiatric disorders and pathological behaviors

Relaxin ligand/receptor systems in the developing teleost fish brain : conserved features with mammals and a platform to address neuropeptide system functions

The relaxins (RLNs) are a group of peptide hormone/neuromodulators that can regulate a wide range of physiological processes ranging from reproduction to brain function. All the family members have originated from a RLN3-like ancestor via different rounds of whole genome and gene specific duplications during vertebrate evolution. In mammals, including human, the divergence of the different family members and the emergence of new members led to the acquisition of specific functions for the various relaxin family peptide and associated receptor genes. In particular, in mammals, it was shown, that the role of RLN3 is correlated to the modulation of arousal, stress responses, emotion, social recognition, and other brain functions, positioning this gene/peptide as a potential therapeutic target for neuropsychiatric disorders. This review highlights the evolutionary conservation of relaxin family peptide and receptor gene expression and their associated brain neural circuits. In the zebrafish, the expression pattern of the different relaxin family members has specific features that are conserved in higher species, including a likely similar functional role for the ancestral RLN3-like gene. The use of different model organisms, particularly the zebrafish, to explore the diversification and conservation of relaxin family ligands and receptor systems, provides a relatively high-throughput platform to identify their specific conserved or differential neuromodulatory roles in higher species including human

Efectos del metilfenidato sobre la ansiedad

The attention deficit disorder with hyperactivity (ADDH) is a widely recognized disorder of unknown etiology. Methylphenidate administration is one of the most commonly used treatments to improve symptoms associated with ADDH. Although it is generally a well tolerated drug, several secondary effects may occur. In particular, this paper will focus on the effects on anxiety, in humans and experimental animal models. It has been shown that acute administration of methylphenidate in adults reduces anxiety, in both animal models and humans. On the other hand, chronic treatment during early ages (postnatal and young subjects) results in higher anxiety in adults. In some cases this effect appears together with higher susceptibility of drug consumption. Thus, we find that, in the literature, methylphenidate is capable of inducing different and opposite effects. Thus, further experiments would be required to elucidate the mechanisms by which methylphenidate exert its actions.El trastorno por déficit de atención/hiperactividad (TDAH) es un trastorno neurológico ampliamente reconoci- do de etiología desconocida. La administración de metilfenidato es uno de los tratamientos más utilizados para la mejora sintomática del TDAH. Aunque es un medicamento en general muy bien tolerado por los pacientes, existen algunos efec- tos secundarios ajenos a los síntomas de la hiperactividad. En particular, esta revisión se centra en revisar los efectos que la administración aguda o crónica del metilfenidato induce en síntomas de ansiedad en humanos y en modelos animales experimentales. Tanto en modelos animales como en humanos, la administración aguda en adultos tiene un efecto an- siolítico. Por otro lado, en modelos animales, la administración crónica en el período posnatal y adolescentes genera es- tados de ansiedad en el adulto, aumentando, además, en algunos casos, aunque no en todos, la propensión a la drogo- dependencia de otras sustancias. Existe disparidad de resultados y serían necesarios más estudios para elucidar los mecanismos por los cuales el metilfenidato ejerce su acción

The role of the cerebellum in drug-cue associative memory: functional interactions with the medial prefrontal cortex

Drug-induced Pavlovian memories are thought to be crucial for drug addiction because they guide behaviour towards environments with drug availability. Drug-related memory depends on persistent changes in dopamine-glutamate interactions in the medial pre- frontal cortex (mPFC), basolateral amygdala, nucleus accumbens core and hippocampus. Recent evidence from our laboratory indi- cated that the cerebellum is also a relevant node for drug-cue associations. In the present study, we tested the role that specific regions of the cerebellum and mPFC play in the acquisition of cocaine-induced preference conditioning. Quinolinic acid was used to manage a permanent deactivation of lobule VIII in the vermis prior to conditioning. Additionally, lidocaine was infused into the prelim- bic and infralimbic (IL) cortices for reversible deactivation before every training session. The present findings show, for the first time, that the cerebellum and mPFC might act together in order to acquire drug-cue Pavlovian associations. Either a dorsal lesion in lobule VIII or an IL deactivation encouraged cocaine-induced preference conditioning. Moreover, simultaneous IL-cerebellar deactivation prevented the effect of either of the separate deactivations. Therefore, similar to the IL cortex, neural activity in the cerebellum may be crucial for ensuring inhibitory control of the expression of cocaine-related memories

MAP/ERK Signaling in Developing Cognitive and Emotional Function and Its Effect on Pathological and Neurodegenerative Processes.

The signaling pathway of the microtubule-associated protein kinase or extracellular regulated kinase (MAPK/ERK) is a common mechanism of extracellular information transduction from extracellular stimuli to the intracellular space. The transduction of information leads to changes in the ongoing metabolic pathways and the modification of gene expression patterns. In the central nervous system, ERK is expressed ubiquitously, both temporally and spatially. As for the temporal ubiquity, this signaling system participates in three key moments: (i) Embryonic development; (ii) the early postnatal period; and iii) adulthood. During embryonic development, the system is partly responsible for the patterning of segmentation in the encephalic vesicle through the FGF8-ERK pathway. In addition, during this period, ERK directs neurogenesis migration and the final fate of neural progenitors. During the early postnatal period, ERK participates in the maturation process of dendritic trees and synaptogenesis. During adulthood, ERK participates in social and emotional behavior and memory processes, including long-term potentiation. Alterations in mechanisms related to ERK are associated with different pathological outcomes. Genetic alterations in any component of the ERK pathway result in pathologies associated with neural crest derivatives and mental dysfunctions associated with autism spectrum disorders. The MAP-ERK pathway is a key element of the neuroinflammatory pathway triggered by glial cells during the development of neurodegenerative diseases, such as Parkinson's and Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis, as well as prionic diseases. The process triggered by MAPK/ERK activation depends on the stage of development (mature or senescence), the type of cellular element in which the pathway is activated, and the anatomic neural structure. However, extensive gaps exist with regards to the targets of the phosphorylated ERK in many of these processes

Mapping cFos expression after cerebellar and medial prefrontal deactivations in rats trained to acquire cocaine-induced preference conditioning

6th Mediterranean Conference of Neuroscience (MNS Malta 2017

Distribution and targets of the relaxin-3 innervation of the septal area in the rat

Neural tracing studies have revealed that the rat medial and lateral septum are targeted by ascending projections from the nucleus incertus, a population of tegmental GABA neurons. These neurons express the relaxin-family peptide, relaxin-3, and pharmacological modulation of relaxin-3 receptors in medial septum alters hippocampal theta rhythm and spatial memory. In an effort to better understand the basis of these interactions, we have characterized the distribution of relaxin-3 fibers/terminals in relation to different septal neuron populations identified using established protein markers. Dense relaxin-3 fiber plexuses were observed in regions of medial septum containing hippocampal-projecting choline acetyltransferase (ChAT)-, neuronal nitric oxide synthase (nNOS)-, and parvalbumin (PV)-positive neurons. In lateral septum (LS), relaxin-3 fibers were concentrated in the ventrolateral nucleus of rostral LS and the ventral nucleus of caudal LS, with sparse labeling in the dorsolateral and medial nuclei of rostral LS, dorsal nucleus of caudal LS, and ventral portion nuclei. Relaxin-3 fibers were also observed in the septofimbrial and triangular septal nuclei. In the medial septum, we observed relaxin-3-immunoreactive contacts with ChAT-, PV-, and glutamate decarboxylase-67-positive neurons that projected to hippocampus, and contacts between relaxin-3 terminals and calbindin- and calretinin-positive neurons. Relaxin-3 colocalized with synaptophysin in nerve terminals in all septal areas, and ultrastructural analysis revealed these terminals were symmetrical and contacted spines, somata, dendritic shafts, and occasionally other axonal terminals. These data predict that this GABA/peptidergic projection modulates septohippocampal activity and hippocampal theta rhythm related to exploratory navigation, defensive and ingestive behaviors, and responses to neurogenic stressors. J. Comp. Neurol. 520:1903–1939, 2012. © 2011 Wiley Periodicals, Inc. Arousal neural pathways of the brain are associated with modulation of behavior in accordance with environmental requirements and a key node in the regulation of arousal is the forebrain septal area. Ascending connections from the medial septum to the hippocampus are proposed to provide “pacemaker” control of hippocampal theta rhythm (Vertes and Kocsis,1997; Hangya et al.,2009), which may underpin goal-oriented behavior (Vinogradova,1995) and plastic changes occurring during the formation of cognitive maps (O'Keefe,1993), whereas descending projections from the lateral septum target a wide variety of subcortical circuits related to visceral and metabolic functions, ranging from aggression, social and sexual behavior, to circadian rhythms (Albert and Chew,1980; Risold and Swanson,1997a; Veenema and Neumann,2007). The septal area plays a central role in controlling hippocampal function, and the importance of the medial septum for “pacemaking” of hippocampal theta rhythm was noted in early studies (Pestche and Stumpf,1962; Andersen et al.,1979; Vinogradova,1995). This view was strengthened by more recent EEG recordings in freely moving rats that demonstrated that the integrity of the entire medial and lateral septum-hippocampal network is critical for the generation of theta rhythm (Nerad and McNaughton,2006). There has also been a consensus over many years that the different types of neurons in the septal area play specific roles in generating theta synchrony, with slow-firing cholinergic neurons facilitating hippocampal firing, and parvalbumin GABAergic neurons that innervate GABAergic hippocampal interneurons driving disinhibition of pyramidal or granule cell inhibition, allowing hippocampal synchrony (Freund and Antal,1988; Freund and Gulyas,1997; Toth et al., 1997a; Wu et al.,2000), although more recent studies have questioned the relative importance of different neuron populations in awake animals (e.g., Simon et al.,2006). Neural tract-tracing studies in the rat by our laboratory and others have demonstrated that the septal area is targeted by ascending projections arising from the nucleus incertus (Goto et al.,2001; Olucha-Bordonau et al.,2003). Neurons of the nucleus incertus contain GABA and a range of peptides, such as cholecystokinin, neurotensin, neuromedin B, and atrial natriuretic peptide (Kubota et al.,1983; Ryan et al., 1995; Olucha-Bordonau et al.,2003; see Ryan et al.,2011, for review). Recent studies have revealed that a large population of nucleus incertus neurons express high levels of the peptide relaxin-3 (RLN3), which is primarily expressed in this region, in addition to smaller adjacent tegmental and midbrain cell groups (Burazin et al.,2002; Bathgate et al.,2003; Tanaka et al.,2005; Ma et al.,2007). The nucleus incertus provides a distinct pattern of ascending projections to raphé nuclei, periaqueductal gray, supramammillary nucleus, several hypothalamic nuclei, midline intralaminar nuclei, habenula, amygdala, hippocampus, the septal area, and the prefrontal cortex (Goto et al.,2001; Olucha-Bordonau et al.,2003). This pattern of efferents overlaps extensively with the forebrain distribution of RLN3-containing nerve fibers (Tanaka et al.,2005; Ma et al.,2007). The native receptor for RLN3 is G-protein coupled receptor-135 (GPCR135) (Liu et al.,2003) or “RXFP3” (Bathgate et al.,2006) and the regional topography of RXFP3 in rat brain is largely consistent with the distribution of RLN3-positive fibers (Ma et al.,2007). The strong connections of the nucleus incertus with a number of brain areas involved in brainstem-diencephalic modulation of hippocampal theta rhythm, such as the median raphé, supramammillary nucleus and the medial septum (Vertes et al., 1993a; Vertes and Kocsis,1997), led us to hypothesize a role for the nucleus incertus in theta rhythm activation. We subsequently demonstrated that stimulation of nucleus incertus in urethane-anesthetized rats increased theta and decreased delta activity of the hippocampus, whereas electrolytic lesion of the nucleus incertus abolished hippocampal theta induced by stimulation of the nucleus reticularis pontis oralis (RPO) (Nunez et al.,2006), a key brainstem generator of hippocampal theta rhythm (Vertes,1981, 1982; Nunez et al.,1991; Vertes et al., 1993b; Vertes and Kocsis,1997). The hippocampal area in which field potentials were recorded receives only sparse inputs from the nucleus incertus, and it was concluded that the influence of the nucleus incertus on hippocampal theta rhythm was most likely mediated by its effects within the medial septum and/or other lower brain structures. In fact, the nucleus incertus is presumed to be the major relay station of RPO inputs to the medial septum (and hippocampus), as there are no direct projections from the RPO to hippocampus (Teruel-Marti et al.,2008). Additionally, RPO stimulation results in theta synchronization in the hippocampus and nucleus incertus, at the same frequency and with a high degree of coherence (Cervera-Ferri et al.,2011). Furthermore, because the nucleus incertus is an RLN3 locus in the brain, we hypothesized that RLN3 might contribute to these effects. Consistent with the presence of RLN3 and RXFP3 in the medial septum, injections of a selective RXFP3 agonist peptide (R3/I5; Liu et al.,2005) into this area increased theta activity of the hippocampal field potential in urethane-anesthetized rats, which was significantly attenuated by prior injection of a selective RXFP3 antagonist peptide, R3(BΔ23-27)R/I5 (Kuei et al.,2007; Ma et al.,2009b). R3/I5 infusion into the medial septum also increased hippocampal theta in rats in a familiar home cage environment, whereas R3(BΔ23-27)R/I5 decreased hippocampal theta in rats exploring a novel enriched context (Ma et al.,2009b). These data support a significant contribution of nucleus incertus and RLN3 inputs to the septum in regulating a fundamental brain activity and associated complex behaviors, and therefore characterization of the anatomical and cellular interactions between these inputs and their targets is required. The goal of the current study, therefore, was to map the distribution of RLN3 positive-fibers throughout the rat septum in relation to particular “landmark” neuron populations. This was achieved in a series of double-labeling experiments using a characterized RLN3 antiserum and antisera for established protein markers expressed by neurons in the septal area. We examined whether RLN3-positive fibers made close contacts with the major septal neuron types in triple- and quadruple-labeling studies combined with confocal microscopy analysis. We also examined the colocalization of RLN3 staining with that for the presynaptic marker, synaptophysin (Jahn et al.,1985), to assess the presence of RLN3 within synapses in the septum. Finally, we conducted ultrastructural analyses of RLN3-positive synapses in the septal area using electron microscopy. The data obtained provide strong anatomical evidence for a role of RLN3 in modulating the activity of specific neurons in the septum that have direct connections with the hippocampus, which may underlie the effects of RLN3/RXFP3 signaling on hippocampal theta rhythm and associated complex behaviors

Nucleus incertus projections to rat medial septum and entorhinal cortex: rare collateralization and septal-gating of temporal lobe theta rhythm activity

Nucleus incertus (NI) neurons in the pontine tegmentum give rise to ascending forebrain projections and express the neuropeptide relaxin-3 (RLN3) which acts via the relaxin-family peptide 3 receptor (RXFP3). Activity in the hippocampus and entorhinal cortex can be driven from the medial septum (MS), and the NI projects to all these centers, where a prominent pattern of activity is theta rhythm, which is related to spatial memory processing. Therefore, we examined the degree of collateralization of NI projections to the MS and the medial temporal lobe (MTL), comprising medial and lateral entorhinal cortex (MEnt, LEnt) and dentate gyrus (DG), and the ability of the MS to drive entorhinal theta in the adult rat. We injected fluorogold and cholera toxin-B into the MS septum and either MEnt, LEnt or DG, to determine the percentage of retrogradely labeled neurons in the NI projecting to both or single targets, and the relative proportion of these neurons that were RLN3-positive ( +). The projection to the MS was threefold stronger than that to the MTL. Moreover, a majority of NI neurons projected independently to either MS or the MTL. However, RLN3 + neurons collateralize significantly more than RLN3-negative (–) neurons. In in vivo studies, electrical stimulation of the NI induced theta activity in the MS and the entorhinal cortex, which was impaired by intraseptal infusion of an RXFP3 antagonist, R3(BΔ23-27)R/I5, particularly at ~ 20 min post-injection. These findings suggest that the MS plays an important relay function in the NI-induced generation of theta within the entorhinal cortex.Funding for open access charge: CRUE-Universitat Jaume IThis research was funded by the Postdoctoral Program of the UJI POSDOC/2021/19 (IG-M); UJI Predoctoral Program PREDOC/2021/19 (MN-S); Fundación Alicia Koplowitz, Spain, grant number 19I436 (FEO-B, FR-B, EC-G); the Spanish Ministerio de Ciencia, Innovación y Universidades, grant number RTI2018-095698-B-I00 (FEO-B, IG-M, FR-B, EC-G); AICO Generalitat Valenciana, grant number AICO/2021/246 (EC-G, FO-B, FR-B), National Health and Medical Research Council of Australia, grant number (ALG), the Spanish Ministerio de Ciencia, Innovación y Universidades, grant number PID2019-107809RB-I00 (AN-M) and Universitat Jaume I, grant numbers UJI-A2017-17 (FR-B) and UJI-B2019-54 (FEO-B).Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. Funding was provided by the Universitat Jaume I, POSDOC/2021/19, PREDOC/2021/19, UJI-A2017-17, Ministerio de Ciencia, Innovación y Universidades, PID2019-107809RB-I00, RTI2018-095698-B-I00, Fundación Alicia Koplowitz, 19I436, Conselleria de Innovación, Universidades, Ciencia y Sociedad Digital, Generalitat Valenciana, AICO/2021/246, National Health and Medical Research Council of Australia, 1067522

From back to front: A functional model for the cerebellar modulation in the establishment of conditioned preferences for cocaine‐related cues

This is the pre-peer reviewed version of the following article: From back to front: A functional model for the cerebellar modulation in the establishment of conditioned preferences for cocaine‐related cues, which has been published in final form at https://doi.org/10.1111/adb.12834. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.It is now increasingly clear that the cerebellum may modulate brain functions altered in drug addiction. We previously demonstrated that cocaine‐induced conditioned preference increased activity at the dorsal posterior cerebellar vermis. Unexpectedly, a neurotoxic lesion at this region increased the probability of cocaine‐induced conditioned preference acquisition. The present research aimed at providing an explanatory model for such as facilitative effect of the cerebellar lesion. First, we addressed a tracing study in which we found a direct projection from the lateral (dentate) nucleus to the ventral tegmental area (VTA) that also receives Purkinje axons from lobule VIII in the vermis. This pathway might control the activity and plasticity of the cortico‐striatal circuitry. Then we evaluated cFos expression in different regions of the medial prefrontal cortex and striatum after a lesion in lobule VIII before conditioning. Additionally, perineuronal net (PNN) expression was assessed to explore whether the cerebellar lesion might affect synaptic stabilization mechanisms in the medial prefrontal cortex (mPFC). Damage in this region of the vermis induced general disinhibition of the mPFC and striatal subdivisions that receive dopaminergic projections, mainly from the VTA. Moreover, cerebellar impairment induced an upregulation of PNN expression in the mPFC. The major finding of this research was to provide an explanatory model for the function of the posterior cerebellar vermis on drug‐related memory. In this model, damage of the posterior vermis would release striatum‐cortical networks from the inhibitory tonic control exerted by the cerebellar cortex over VTA, thereby promoting drug effects

The African striped mouse Lemniscomys barbarus as a model for aggression. Brain areas activated by agonistic encounters

During agonistic behavior several brain areas became differentially activated depending on the role the subject is taking. Several areas are mostly activated during the offender role and several others are activated if the subject plays a defensive role. The main goal of this work is to study in detail the anatomic areas involved in agonistic behavior using a novel animal model, the striped mouse Lemniscomys barbarus, a North African diurnal rodent well known by its natural high aggressiveness toward conspecifics. After social encounters, neural activation in brain areas related to agonistic behavior was measured by c-fos immunostaining. The encounters were recorded and behaviors related to the encounter were analyzed. We differentiated between the aggressive behavior (offender) and escape behavior (defender or defeated). Our results showed that conspecific confrontation induced general c-fos activation in both offender and defender in all measured areas in comparison with non-confronted control. Differences in neural activity between offender and defender were observed specifically in the lateral, cortical and medial amygdala, suprachiasmatic nucleus and the nucleus incertus, suggesting a potential role of these areas in displaying different kinds of behavior during conspecific confrontation. We found that, while in the lateral, medial and cortical amygdala defenders express significantly more c-fos than offenders, in the nucleus incertus of the brainstem the differential activation is just the opposite, Additionally, defenders display significantly more freezing than offenders. This work provides data showing that Lemniscomys barbarus is a widely useful model to study the anatomic background supporting agonistic behavior.This research was supported by the following grants: 51 0935-Tempus-1-2010, TEMPUS IV EU (RB), Generalitat Valenciana AICO/2015/042; Universitat Jaume I P1·1A2014-06 (AMS)