Hypothalamic CRH neurons represent physiological memory of positive and negative experience.

Recalling a salient experience provokes specific behaviors and changes in the physiology or internal state. Relatively little is known about how physiological memories are encoded. We examined the neural substrates of physiological memory by probing CRHPVN neurons of mice, which control the endocrine response to stress. Here we show these cells exhibit contextual memory following exposure to a stimulus with negative or positive valence. Specifically, a negative stimulus invokes a two-factor learning rule that favors an increase in the activity of weak cells during recall. In contrast, the contextual memory of positive valence relies on a one-factor rule to decrease activity of CRHPVN neurons. Finally, the aversive memory in CRHPVN neurons outlasts the behavioral response. These observations provide information about how specific physiological memories of aversive and appetitive experience are represented and demonstrate that behavioral readouts may not accurately reflect physiological changes invoked by the memory of salient experiences.

Distinct acute stressors exert an antagonistic effect on complex grooming during novelty habituation in rats.

Grooming is a common readout in multiple rat models of neuropsychiatric diseases. It is usually associated with distress and negative emotionality, but also with emotional de-arousal after stress. These seemingly conflicting interpretations may result from specific grooming sequences appearing at different arousal levels and during distinct phases of the stress response. To further explore this hypothesis, we analyzed how distinct stressors affect grooming syntaxis and kinetics. To that end, we explored the independent and interacting effects of foot shocks, corticosterone (CORT), and novelty on exploratory activity, grooming, and ultrasonic vocalizations (USVs) in an open-field test (OF). Wistar rats were intraperitoneally injected either with vehicle or CORT, placed in a chamber where half of them were foot-shocked and then assessed in the OF. The next day, animals were re-exposed to the shock chamber and then tested in the OF without receiving any treatment. On day 1, foot shocks and -to a less extent CORT- increased freezing and inhibited rearing in the chamber, but only foot shocks increased distress USVs. In the OF, both treatments suppressed complex grooming, with foot-shocks also inhibiting exploration and CORT marginally reducing rearing. On day 2, foot-shocked rats showed conditioned fear when re-exposed to the chamber. When tested in the OF, foot-shocked and CORT-treated animals still showed low levels of complex grooming, with the former group also showing increased distress USVs. In this study, all different stressors inhibited complex grooming, suggesting an inverse association between these grooming subtypes and negative emotionality.

The environmental enrichment model revisited: A translatable paradigm to study the stress of our modern lifestyle.

Mounting evidence shows that physical activity, social interaction and sensorimotor stimulation provided by environmental enrichment (EE) exert several neurobehavioural effects traditionally interpreted as enhancements relative to standard housing (SH) conditions. However, this evidence rather indicates that SH induces many deficits, which could be ameliorated by exposing animals to an environment vaguely mimicking some features of their wild habitat. Rearing rodents in social isolation (SI) can aggravate such deficits, which can be restored by SH or EE. It is not surprising, therefore, that most preclinical stress models have included severe and unnatural stressors to produce a stress response prominent enough to be distinguishable from SH or SI-frequently used as control groups. Although current stress models induce a stress-related phenotype, they may fail to represent the stress of our urban lifestyle characterized by SI, poor housing and working environments, sedentarism, obesity and limited access to recreational activities and exercise. In the following review, we discuss the stress of living in urban areas and how exposures to and performing activities in green environments are stress relievers. Based on the commonalities between human and animal EE, we discuss how models of housing conditions (e.g., SI-SH-EE) could be adapted to study the stress of our modern lifestyle. The housing conditions model might be easy to implement and replicate leading to more translational results. It may also contribute to accomplishing some ethical commitments by promoting the refinement of procedures to model stress, diminishing animal suffering, enhancing animal welfare and eventually reducing the number of experimental animals needed.

Muscarinic regulation of self-grooming behavior and ultrasonic vocalizations in the context of open-field habituation in rats.

Laboratory rats repeatedly exposed to an open field (OF) apparatus display increasingly high levels of grooming -especially that characterized by long and complex sequences- which has been taken as an additional index of novelty habituation. We hypothesized that disrupting such a learning process by administering an amnesic drug as the antimuscarinic scopolamine (SCP) could delay the appearance of more complex grooming subtypes. Thus, rats were pretreated either with SCP (15 mg/kg or 30 mg/kg) or vehicle (VEH) upon four one-day apart OF (OF1-4). On a fifth assessment, all rats received VEH to analyze the likely carry-over effect of SCP. Finally, we measured 50-kHz and 22-kHz ultrasonic vocalizations (USVs) as reliable markers of positive and negative emotionality, respectively. We found that SCP increased locomotion during OF1 and reduced rearing on OF1-OF4, causing no disruption in habituation over tests. SCP prevented the increase of total grooming time by inhibiting complex grooming subtypes and promoting short cephalic sequences. Despite the SCP-induced alterations on grooming agreed with our hypotheses, those changes may have resulted from a motor impairment that could have also affected rearing behavior. Additionally, SCP suppressed 50-kHz USVs while marginally increased 22-kHz calls. Once SCP was withdrawn, rearing, grooming, and some 50-kHz USVs subtypes returned to VEH levels, suggesting that novelty habituation occurred despite the SCP administration. Altogether, that mixed profile of SCP-induced behavioral changes may derive from the complex interplay between the contrasting action of SCP on different brain regions and the doses here used.

The cage test as an easy way to screen and evaluate spontaneous activity in preclinical neuroscience studies.

Within behavioral neuroscience, subjects used to be randomly assigned to the experimental groups based on the premise that interindividual variability will be homogeneously distributed. However, the equivalence offered by randomization diminishes in small samples, which is the case for most experiments in the field. In rodents, it is well-recognized that individual differences in psychomotor reactivity, risk-assessment behaviors, and emotional responsiveness modulate the effects of different pharmacological and non-pharmacological treatments. For that reason, knowing such differences before the experiment provides highly valuable information for balancing the groups so that the interindividual variability is equally distributed within the groups without excluding subjects as far as possible. Because unconditioned anxiety tests such as the open-field (OF) and the elevated plus-maze are commonly used within experimental procedures, we developed a strategy to explore the rat's behavioral phenotype by assessing it in a very innocuous testing context: a housing cage.•We offer a very straightforward protocol for assessing spontaneous, novelty-induced reactivity in rodents.•We describe its implementation, analysis, and use, as well as some suggestions about key behavioral readouts for the group allocation procedure.•The current protocol provides an alternative strategy to assess a reasonably wide range of behavioral outcomes, most of which are of great interest in modeling different neuropsychiatric disorders.

Neurobehavioral Effects of Restricted and Unpredictable Environmental Enrichment in Rats.

To study how motivational factors modulate experience-dependent neurobehavioral plasticity, we modify a protocol of environmental enrichment (EE) in rats. We assumed that the benefits derived from EE might vary according to the level of incentive salience attributed to it. To enhance the rewarding properties of EE, access to the EE cage varied randomly from 2 to 48 h for 30 days (REE). The REE group was enriched only 50% of the time and was compared to standard housing and continuous EE (CEE) groups. As behavioral readout, we analyzed the spontaneous activity and the ultrasonic vocalizations (USVs) within the EE cage weekly, and in the open field test at the end of the experiment. In the cage, REE increased the utilization of materials, physical activity, and the rate of appetitive USVs. In the OF, the CEE-induced enhancements in novelty habituation and social signaling were equaled by the REE. At the neural level, we measured the expression of genes related to neural plasticity and epigenetic regulations in different brain regions. In the dorsal striatum and hippocampus, REE upregulated the expression of the brain-derived neurotrophic factor, its tropomyosin kinase B receptor, and the DNA methyltransferase 3A. Altogether, our results suggest that the higher activity within the cage and the augmented incentive motivation provoked by the REE boosted its neurobehavioral effects equaling or surpassing those observed in the CEE condition. As constant exposures to treatments or stimulating environments are virtually impossible for humans, restricted EE protocols would have greater translational value than traditional ones.

Acute stress differentially affects grooming subtypes and ultrasonic vocalisations in the open-field and home-cage test in rats.

Grooming behaviour in rodents has been associated with emotional distress, especially in unfamiliar and aversive contexts. However, the biological function of grooming in such situations is still unclear. We hypothesised that particular grooming subtypes are differentially associated with the stress response. Here, we investigated the effects of an acute stress exposure on grooming and ultrasonic vocalisations (USVs) assessed on different testing contexts varying in the level of familiarity. To this aim, footshocked and non-footshocked rats were tested for 20 min on one of the following conditions: an unfamiliar open-field test, a familiar open-field test, and an individual home cage filled with bedding. We found that footshock stress slightly decreased complex grooming sequences while increased cephalic grooming. Stress induced a negative affective state inferred from an increase and decrease of 22-kHz and 50-kHz calls, respectively. The latter USVs correlated positively with the complex grooming subtypes. Altogether, a detailed analysis of grooming seems necessary for elucidating its diverse biological functions. Nevertheless, footshock stress and testing conditions produced weaker-than-expected effects, possibly because the time elapsed between footshocks and behavioural testing was too short for eliciting a full stress response, and because the simple footshock-chamber experience may have impeded detecting stronger effects of familiarity.

Age-dependent differences on neurochemistry and behavior in rats raised with low and high levels of maternal care.

In laboratory rats, naturally-occurring variations in maternal care have been used to study the neurobehavioral consequences of maternal nursing and to model the early-life adversity associated with many psychiatric disorders. This study aimed to determine the role of maternal care on behavior and monoamine concentrations at the prepubertal and young adulthood ages. We observed the licking/grooming (LG) behavior of Sprague-Dawley (SD) dams and assigned the litter to either low (LLG) or high (HLG) LG groups. Behavioral testing in the male offspring consisted of the open-field test, the elevated plus-maze, and the forced swimming test. Afterward, neurotransmitters contents were measured in the prefrontal cortex, the nucleus accumbens, the amygdala, and the hippocampus. We found that at the prepubertal stage, the effects of maternal care were only noticeable in the elevated plus-maze and the serotonin concentration in the nucleus accumbens. At adulthood, body weight and monoamines contents increased substantially in LLG rats. Specifically, they showed higher serotonin contents with a reduced turnover in almost all brain regions, followed by higher contents of norepinephrine and dopamine, especially in the nucleus accumbens. Changes in monoamines concentrations seem to be independent of the behavioral phenotype shaped by variations in maternal care, as behavioral effects were somewhat weak in both experiments. If higher monoamines contents in LLG rats represent an adaptive mechanism to deal with further adverse events, the behavioral paradigms used here were insufficiently challenging to bring out noticeable differences, at least in SD rats.

De la neuroplasticidad a las propuestas aplicadas: estimulación temprana y su implementación en Costa Rica / From Neuroplasticity to Applied Proposals: Early Stimulation and Its Implementation in Costa Rica

Resumen La discusión en torno a la influencia del ambiente sobre la ontogenia ha alimentado la interrogante sobre cuál es el grado en el que, a través de la manipulación del contexto, se modifican las características de los individuos. Actualmente, la evidencia científica desde distintos campos (e.g., Psicología del desarrollo, Neurociencias) describe cómo el ambiente es capaz de modular los procesos del desarrollo y las distintas capacidades del cerebro, así como los mecanismos plásticos que subyacen a dicha modulación. Con base en esta evidencia, distintas aproximaciones metodológicas orientadas a la estimulación temprana (ET) se han propuesto potenciar el desarrollo o remediar problemas que se presentan durante las etapas tempranas del ciclo vital. En este contexto, se brinda una revisión del tema y se ofrece un marco teórico general sobre los antecedentes y sobre los principios que sustentan la estimulación del sistema nervioso (i.e., plasticidad cerebral). Además, a través de una aproximación empírica y un proceso de revisión bibliográfica, se presenta la evidencia disponible de algunos de los métodos de mayor conocimiento/uso en Costa Rica (i.e., Doman- Delacato, Snoezelen®, Point y Bebé Políglota). Al recapitular los alcances y las limitaciones de la ET, se concluye que es necesario sistematizar las experiencias profesionales de forma tal que permitan abrir un debate académico sobre el tema.

Abstract The discussion about environmental influence on ontogeny has fueled the question about how much context manipulation can regulate individuals' characteristics. Today, scientific evidence from different fields (e.g., developmental psychology, neuroscience) describes not only how environment can modulate brain development and function, but also the plastic mechanisms involved. In consequence, different methodological approximations of early stimulation (ES) have arisen, although they are not necessarily based on solid empirical evidence. In this context, a brief approximation to the ES background is provided, as well as a general framework about brain plasticity. In addition, the theoretical and practical perspective of the ES practitioners is also described by detailing the empirical evidence around its most known/used variants in Costa Rica (i.e., Doman-Delacato, Snoezelen®, Point and Bebé políglota). Finally, bringing up the scope and limitations of ES, we conclude that the professional experiences need to be systematized, in order to open an academic debate on the subject.

Age-dependent effects of environmental enrichment on spatial memory and neurochemistry.

Although aging and environmental stimulation are well-known to affect cognitive abilities, the question of whether aging effects can be distinguished in already-mature adult rats has not been fully addressed. In the present study, therefore, young and mature adult rats were housed in either enriched or standard conditions (EE or SC) for three months. Open-field (OFT) and radial-maze (RM) behavior, and ex-vivo contents of GABA and glutamate in hippocampus, and of dopamine and DOPAC in ventral striatum (VS) were analyzed and compared between the four groups. In OFT, young rats were more active than mature adults irrespective of the housing condition. Surprisingly, in the RM test, mature adults outperformed young counterparts except for the young-enriched rats, which showed a progressive improvement in RM performance. At the neurochemical level, young EE rats showed higher hippocampal glutamate and GABA concentrations, and DA turnover in VS, which correlated with RM performance. Altogether, the behavioral and cognitive strategies underlying habituation learning and spatial memory seem to be qualitatively different between the two ages analyzed. These results challenge the assumption that mature adult animals are always worse in learning and memory tasks. However, young rats benefited more from the social and physical stimulation provided by the enrichment than mature adult counterparts. The latter effect was evident not just on behavior, but also on brain neurochemistry.