Complex Housing, but Not Maternal Deprivation Affects Motivation to Liberate a Trapped Cage-Mate in an Operant Rat Task.

Early life environment influences the development of various aspects of social behavior, particularly during sensitive developmental periods. We studied how challenges in the early postnatal period or (early) adolescence affect pro-social behavior. To this end, we designed a lever-operated liberation task, to be able to measure motivation to liberate a trapped conspecific (by progressively increasing required lever pressing for door-opening). Liberation of the trapped rat resulted either in social contact or in liberation into a separate compartment. Additionally, a condition was tested in which both rats could freely move in two separate compartments and lever pressing resulted in social contact. When partners were not trapped, rats were more motivated to press the lever for opening the door than in either of the trapped configurations. Contrary to our expectations, the trapped configuration resulted in a reduced motivation to act. Early postnatal stress (24 h maternal deprivation on postnatal day 3) did not affect behavior in the liberation task. However, rearing rats from early adolescence onwards in complex housing conditions (Marlau cages) reduced the motivation to door opening, both in the trapped and freely moving conditions, while the motivation for a sucrose reward was not affected.

Early Detection of Exposure to Toxic Chemicals Using Continuously Recorded Multi-Sensor Physiology.

Early detection of exposure to a toxic chemical, e.g., in a military context, can be life-saving. We propose to use machine learning techniques and multiple continuously measured physiological signals to detect exposure, and to identify the chemical agent. Such detection and identification could be used to alert individuals to take appropriate medical counter measures in time. As a first step, we evaluated whether exposure to an opioid (fentanyl) or a nerve agent (VX) could be detected in freely moving guinea pigs using features from respiration, electrocardiography (ECG) and electroencephalography (EEG), where machine learning models were trained and tested on different sets (across subject classification). Results showed this to be possible with close to perfect accuracy, where respiratory features were most relevant. Exposure detection accuracy rose steeply to over 95% correct during the first five minutes after exposure. Additional models were trained to correctly classify an exposed state as being induced either by fentanyl or VX. This was possible with an accuracy of almost 95%, where EEG features proved to be most relevant. Exposure detection models that were trained on subsets of animals generalized to subsets of animals that were exposed to other dosages of different chemicals. While future work is required to validate the principle in other species and to assess the robustness of the approach under different, realistic circumstances, our results indicate that utilizing different continuously measured physiological signals for early detection and identification of toxic agents is promising.

Pharmacokinetics and efficacy of atropine sulfate/obidoxime chloride co-formulation against VX in a guinea pig model.

Nerve agent exposure is generally treated by an antidote formulation composed of a muscarinic antagonist, atropine sulfate (ATR), and a reactivator of acetylcholinesterase (AChE) such as pralidoxime, obidoxime (OBI), methoxime, trimedoxime or HI-6 and an anticonvulsant. Organophosphates (OPs) irreversibly inhibit AChE, the enzyme responsible for termination of acetylcholine signal transduction. Inhibition of AChE leads to overstimulation of the central and peripheral nervous system with convulsive seizures, respiratory distress and death as result. The present study evaluated the efficacy and pharmacokinetics (PK) of ATR/OBI following exposure to two different VX dose levels. The PK of ATR and OBI administered either as a single drug, combined treatment but separately injected, or administered as the ATR/OBI co-formulation, was determined in plasma of naïve guinea pigs and found to be similar for all formulations. Following subcutaneous VX exposure, ATR/OBI-treated animals showed significant improvement in survival rate and progression of clinical signs compared to untreated animals. Moreover, AChE activity after VX exposure in both blood and brain tissue was significantly higher in ATR/OBI-treated animals compared to vehicle-treated control. In conclusion, ATR/OBI has been proven to be efficacious against exposure to VX and there were no PK interactions between ATR and OBI when administered as a co-formulation.

Pro-social preference in an automated operant two-choice reward task under different housing conditions: Exploratory studies on pro-social decision making.

In this study, we aimed to develop a behavioral task that measures pro-social decision making in rats. A fully automated, operant pro-social two-choice task is introduced that quantifies pro-social preferences for a mutual food reward in a set-up with tightly controlled task contingencies. Pairs of same-sex adult Wistar rats were placed in an operant chamber divided into two compartments (one rat per compartment), separated by a transparent barrier with holes that allowed the rats to see, hear, smell, but not touch each other. Test rats could earn a sucrose pellet either for themselves (own reward) or for themselves and the partner (both reward) by means of lever pressing. On average, male rats showed a 60 % preference for the lever that yielded a food reward for both themselves and their partner. In contrast, females did not show lever preference, regardless of the estrous cycle phase. Next, the impact of juvenile environmental factors on male rat social decision making was studied. Males were group-housed from postnatal day 26 onwards in complex housing Marlau™ cages that provided social and physical enrichment and stimulation in the form of novelty. Complex housed males did not show a preference for the pro-social lever.

Reinforcement learning across the rat estrous cycle.

Reinforcement learning, the process by which an organism flexibly adapts behavior in response to reward and punishment, is vital for the proper execution of everyday behaviors, and its dysfunction has been implicated in a wide variety of mental disorders. Here, we use computational trial-by-trial analysis of data of female rats performing a probabilistic reward learning task and demonstrate that core computational processes underlying value-based decision making fluctuate across the estrous cycle, providing a neuroendocrine substrate by which gonadal hormones may influence adaptive behavior.

Effects of Maternal Deprivation and Complex Housing on Rat Social Behavior in Adolescence and Adulthood.

Early life context and stressful experiences are known to increase the risk of developing psychiatric disorders later in life, including disorders with deficits in the social domain. Our study aimed to investigate the influence of early life environment on social behavior in a well-controlled animal model. To this end we tested the effects of maternal deprivation (MD) on rat social play behavior in adolescence and social interaction in adulthood. Additionally, we provided a stimulating environment during adolescence (complex housing) as a potential intervention to diminish the effects of early life stress. Male and female Wistar rats were deprived from their mother for 24 h on postnatal day 3 (PND 3) or were left undisturbed. Complex housing started 5 days after weaning and consisted of housing 10 same-sex conspecifics in large, two-floor MarlauTM cages until the end of the study. Social play behavior in adolescence was tested under different conditions (3 h vs. 24 h social isolation prior to testing). Maternally deprived males - but not females - showed a longer latency to play and a decreased total amount of social play behavior, after a 24 h isolation period. In adulthood, social discrimination was impaired in deprived male and female rats in the three-chamber social approach task. Complex housing did not moderate the effects of MD, but in itself induced a strong behavioral phenotype. Both complex housed males and females hardly displayed any play behavior after a 3 h isolation period. However, after 24 h of isolation, these animals showed shorter latencies to engage in social play behavior. Only complex housed males truly showed more social play behavior here, while showing less social interest in adulthood. We conclude that MD has mild negative effects on social behavior in adolescence and adulthood, which are not counteracted by complex housing. Complex housing induces a specific phenotype associated with rapid habituation; a lack of social play after short isolation periods, while increasing play behavior after a prolonged period of isolation in adolescence, and less social interest, paired with intact social discrimination in adulthood. In both early life settings, males seem to be more influenced by the early life environment compared to females.

Counteractive effects of antenatal glucocorticoid treatment on D1 receptor modulation of spatial working memory.

RATIONALE: Antenatal exposure to the glucocorticoid dexamethasone dramatically increases the number of mesencephalic dopaminergic neurons in rat offspring. However, the consequences of this expansion in midbrain dopamine (DA) neurons for behavioural processes in adulthood are poorly understood, including working memory that depends on DA transmission in the prefrontal cortex (PFC). OBJECTIVES: We therefore investigated the influence of antenatal glucocorticoid treatment (AGT) on the modulation of spatial working memory by a D1 receptor agonist and on D1 receptor binding and DA content in the PFC and striatum. METHODS: Pregnant rats received AGT on gestational days 16-19 by adding dexamethasone to their drinking water. Male offspring reared to adulthood were trained on a delayed alternation spatial working memory task and administered the partial D1 agonist SKF38393 (0.3-3 mg/kg) by systemic injection. In separate groups of control and AGT animals, D1 receptor binding and DA content were measured post-mortem in the PFC and striatum. RESULTS: SKF38393 impaired spatial working memory performance in control rats but had no effect in AGT rats. D1 binding was significantly reduced in the anterior cingulate cortex, prelimbic cortex, dorsal striatum and ventral pallidum of AGT rats compared with control animals. However, AGT had no significant effect on brain monoamine levels. CONCLUSIONS: These findings demonstrate that D1 receptors in corticostriatal circuitry down-regulate in response to AGT. This compensatory effect in D1 receptors may result from increased DA-ergic tone in AGT rats and underlie the resilience of these animals to the disruptive effects of D1 receptor activation on spatial working memory.

Mifepristone Treatment during Early Adolescence Fails to Restore Maternal Deprivation-Induced Deficits in Behavioral Inhibition of Adult Male Rats.

Early life adversity has a profound impact on brain development and later life health. Animal models have provided insight how early life stress programs stress responsiveness and might contribute to the development of psychiatric disorders. In the present study, the long-term effects of maternal deprivation (MD) on behavioral inhibition and attention were examined in adult male Wistar rats. To this end animals were tested in the 5-choice serial reaction time task (5-choice SRTT). We also explored the potential of a 3-day treatment with the glucocorticoid receptor (GR) antagonist mifepristone during early adolescence to normalize putative behavioral effects of early life stress. Deprivation of the mother for 24 h on postnatal day (PND) 3 led to a modest but significant increase in premature responses in the 5-choice SRTT, but did not affect measures of attention. Body weight was lower in deprived animals from weaning until the start of testing. Early adolescent mifepristone treatment (PND 26-28) did not influence performance on the 5-choice SRTT and did not mitigate the deprivation-related impairment in behavioral inhibition. Our results indicate that MD leads to impaired behavioral inhibition, and that mifepristone treatment during early adolescence does not normalize the behavioral changes caused by early life stress.

Complex Living Conditions Impair Behavioral Inhibition but Improve Attention in Rats.

Rapid adaptation to changes, while maintaining a certain level of behavioral inhibition is an important feature in every day functioning. How environmental context and challenges in life can impact on the development of this quality is still unknown. In the present study, we examined the effect of a complex rearing environment during adolescence on attention and behavioral inhibition in adult male rats. We also tested whether these effects were affected by an adverse early life challenge, maternal deprivation (MD). We found that animals that were raised in large, two floor Marlau(TM) cages, together with 10 conspecifics, showed improved attention, but impaired behavioral inhibition in the 5-choice serial reaction time task. The early life challenge of 24 h MD on postnatal day 3 led to a decline in bodyweight during adolescence, but did not by itself influence responses in the 5-choice task in adulthood, nor did it moderate the effects of complex housing. Our data suggest that a complex rearing environment leads to a faster adaptation to changes in the environment, but at the cost of lower behavioral inhibition.

Context modulates outcome of perinatal glucocorticoid action in the brain.

Prematurely born infants may be at risk, because of inadequate maturation of tissues. If there are signs of preterm birth, it has become common practice therefore to treat either antenatally the mother or postnatally the infant with glucocorticoids to accelerate tissue development, particularly of the lung. However, this life-saving early glucocorticoid treatment was found to increase the risk of adverse outcome in later life. In one animal study, the authors reported a 25% shorter lifespan of rats treated as newborns with the synthetic glucocorticoid dexamethasone, but so far this finding has not been replicated. After a brief clinical introduction, we discuss studies in rodents designed to examine how perinatal glucocorticoid action affects the developing brain. It appears that the perinatal action of the glucocorticoid depends on the context and the timing as well as the type of administered steroid. The type of steroid is important because the endogenous glucocorticoids cortisol and corticosterone bind to two distinct receptor populations, i.e., mineralocorticoid and glucocorticoid receptors (GR), while synthetic glucocorticoids predominantly bind to the GR. In addition, if given antenatally hydrocortisone is inactivated in the placenta by 11ß-HSD type 2, and dexamethasone is not. With respect to timing, the outcome of glucocorticoid effects is different in early vs. late phases of brain development. The context refers to the environmental input that can affect the susceptibility to glucocorticoid action in the newborn rodent brain; early handling of pups and maternal care obliterate effects of post-natal dexamethasone treatment. Context also refers to coping with environmental conditions in later life, for which the individual may have been programed epigenetically by early-life experience. This knowledge of determinants affecting the outcome of perinatal glucocorticoid exposure may have clinical implications for the treatment of prematurely born infants.

Deletion of the forebrain mineralocorticoid receptor impairs social discrimination and decision-making in male, but not in female mice.

Social interaction with unknown individuals requires fast processing of information to decide whether it is friend or foe. This process of discrimination and decision-making is stressful and triggers secretion of corticosterone activating mineralocorticoid receptor (MR) and glucocorticoid receptor (GR). The MR is involved in appraisal of novel experiences and risk assessment. Recently, we have demonstrated in a dual-solution memory task that MR plays a role in the early stage of information processing and decision-making. Here we examined social approach and social discrimination in male and female mice lacking MR from hippocampal-amygdala-prefrontal circuitry and controls. The social approach task allows the assessment of time spent with an unfamiliar mouse and the ability to discriminate between familiar and unfamiliar conspecifics. The male and female test mice were both more interested in the social than the non-social experience and deletion of their limbic MR increased the time spent with an unfamiliar mouse. Unlike controls, the male MR(CaMKCre) mice were not able to discriminate between an unfamiliar and the familiar mouse. However, the female MR mutant had retained the discriminative ability between unfamiliar and familiar mice. Administration of the MR antagonist RU28318 to male mice supported the role of the MR in the discrimination between an unfamiliar mouse and a non-social stimulus. No effect was found with a GR antagonist. Our findings suggest that MR is involved in sociability and social discrimination in a sex-specific manner through inhibitory control exerted putatively via limbic-hippocampal efferents. The ability to discriminate between familiar and unfamiliar conspecifics is of uttermost importance for territorial defense and depends on a role of MR in decision-making.

Spatial learning of female mice: a role of the mineralocorticoid receptor during stress and the estrous cycle.

Corticosterone facilitates behavioral adaptation to a novel experience in a coordinate manner via mineralocorticoid (MR) and glucocorticoid receptors (GR). Initially, MR mediates corticosterone action on appraisal processes, risk assessment and behavioral flexibility and then, GR activation promotes consolidation of the new information into memory. Here, we studied on the circular holeboard (CHB) the spatial performance of female mice with genetic deletion of MR from the forebrain (MR(CaMKCre)) and their wild type littermates (MR(flox/flox) mice) over the estrous cycle and in response to an acute stressor. The estrous cycle had no effect on the spatial performance of MR(flox/flox) mice and neither did the acute stressor. However, the MR(CaMKCre) mutants needed significantly more time to find the exit and made more hole visit errors than the MR(flox/flox) mice, especially when in proestrus and estrus. In addition, stressed MR(CaMKCre) mice in estrus had a shorter exit latency than the control estrus MR(CaMKCre) mice. About 70% of the female MR(CaMKCre) and MR(flox/flox) mice used a hippocampal (spatial, extra maze cues) rather than the caudate nucleus (stimulate-response, S-R, intra-maze cue) strategy and this preference did neither change over the estrous cycle nor after stress. However, stressed MR(CaMKCre) mice using the S-R strategy needed significantly more time to find the exit hole as compared to the spatial strategy using mice suggesting that the MR could be needed for the stress-induced strategy switch toward a spatial strategy. In conclusion, the results suggest that loss of MR interferes with performance of a spatial task especially when estrogen levels are high suggesting a strong interaction between stress and sex hormones.