Effects of acute stress on reward processing: A comprehensive meta-analysis of rodent and human studies.

Stressors can initiate a cascade of central and peripheral changes that modulate mesocorticolimbic dopaminergic circuits and, ultimately, behavioral response to rewards. Driven by the absence of conclusive evidence on this topic and the Research Domain Criteria framework, random-effects meta-analyses were adopted to quantify the effects of acute stressors on reward responsiveness, valuation, and learning in rodent and human subjects. In rodents, acute stress reduced reward responsiveness (g = -1.43) and valuation (g = -0.32), while amplifying reward learning (g = 1.17). In humans, acute stress had marginal effects on valuation (g = 0.25), without affecting responsiveness and learning. Moderation analyses suggest that acute stress neither has unitary effects on reward processing in rodents nor in humans and that the duration of the stressor and specificity of reward experience (i.e., food vs drugs) may produce qualitatively and quantitatively different behavioral endpoints. Subgroup analyses failed to reduce heterogeneity, which, together with the presence of publication bias, pose caution on the conclusions that can be drawn and point to the need of guidelines for the conduction of future studies in the field.

Prefrontal Dopamine in Flexible Adaptation to Environmental Changes: A Game for Two Players.

Deficits in cognitive flexibility have been characterized in affective, anxiety, and neurodegenerative disorders. This paper reviews data, mainly from studies on animal models, that support the existence of a cortical-striatal brain circuit modulated by dopamine (DA), playing a major role in cognitive/behavioral flexibility. Moreover, we reviewed clinical findings supporting misfunctioning of this circuit in Parkinson's disease that could be responsible for some important non-motoric symptoms. The reviewed findings point to a role of catecholaminergic transmission in the medial prefrontal cortex (mpFC) in modulating DA's availability in the nucleus accumbens (NAc), as well as a role of NAc DA in modulating the motivational value of natural and conditioned stimuli. The review section is accompanied by a preliminary experiment aimed at testing weather the extinction of a simple Pavlovian association fosters increased DA transmission in the mpFC and inhibition of DA transmission in the NAc.

A mouse model of the 3-hit effects of stress: Genotype controls the effects of life adversities in females.

Helplessness is a dysfunctional coping response to stressors associated with different psychiatric conditions. The present study tested the hypothesis that early and adult adversities cumulate to produce helplessness depending on the genotype (3-hit hypothesis of psychopathology). To this aim, we evaluated whether Chronic Unpredictable Stress (CUS) differently affected coping and mesoaccumbens dopamine (DA) responses to stress challenge by adult mice of the C57BL/6J (B6) and DBA/2J (D2) inbred strains depending on early life experience (Repeated Cross Fostering, RCF). Three weeks of CUS increased the helplessness expressed in the Forced Swimming Test (FST) and the Tail Suspension Test by RCF-exposed female mice of the D2 strain. Moreover, female D2 mice with both RCF and CUS experiences showed inhibition of the stress-induced extracellular DA outflow in the Nucleus Accumbens, as measured by in vivo microdialysis, during and after FST. RCF-exposed B6 mice, instead, showed reduced helplessness and increased mesoaccumbens DA release. The present results support genotype-dependent additive effects of early experiences and adult adversities on behavioral and neural responses to stress by female mice. To our knowledge, this is the first report of a 3-hit effect in an animal model. Finally, the comparative analyses of behavioral and neural phenotypes expressed by B6 and D2 mice suggest some translationally relevant hypotheses of genetic risk factors for psychiatric disorders.

GABAergic miR-34a regulates Dorsal Raphè inhibitory transmission in response to aversive, but not rewarding, stimuli.

The brain employs distinct circuitries to encode positive and negative valence stimuli, and dysfunctions of these neuronal circuits have a key role in the etiopathogenesis of many psychiatric disorders. The Dorsal Raphè Nucleus (DRN) is involved in various behaviors and drives the emotional response to rewarding and aversive experiences. Whether specific subpopulations of neurons within the DRN encode these behaviors with different valence is still unknown. Notably, microRNA expression in the mammalian brain is characterized by tissue and neuronal specificity, suggesting that it might play a role in cell and circuit functionality. However, this specificity has not been fully exploited. Here, we demonstrate that microRNA-34a (miR-34a) is selectively expressed in a subpopulation of GABAergic neurons of the ventrolateral DRN. Moreover, we report that acute exposure to both aversive (restraint stress) and rewarding (chocolate) stimuli reduces GABA release in the DRN, an effect prevented by the inactivation of DRN miR-34a or its genetic deletion in GABAergic neurons in aversive but not rewarding conditions. Finally, miR-34a inhibition selectively reduced passive coping with severe stressors. These data support a role of miR-34a in regulating GABAergic neurotransmitter activity and behavior in a context-dependent manner and suggest that microRNAs could represent a functional signature of specific neuronal subpopulations with valence-specific activity in the brain.

Role of Stress-Related Dopamine Transmission in Building and Maintaining a Protective Cognitive Reserve.

This short review presents the hypothesis that stress-dependent dopamine (DA) transmission contributes to developing and maintaining the brain network supporting a cognitive reserve. Research has shown that people with a greater cognitive reserve are better able to avoid symptoms of degenerative brain changes. The paper will review evidence that: (1) successful adaptation to stressors involves development and stabilization of effective but flexible coping strategies; (2) this process requires dynamic reorganization of functional networks in the adult brain; (3) DA transmission is amongst the principal mediators of this process; (4) age- and disease-dependent cognitive impairment is associated with dysfunctional connectivity both between and within these same networks as well as with reduced DA transmission.

Repetitive and Inflexible Active Coping and Addiction-like Neuroplasticity in Stressed Mice of a Helplessness-Resistant Inbred Strain.

Dysfunctional coping styles are involved in the development, persistence, and relapse of psychiatric diseases. Passive coping with stress challenges (helplessness) is most commonly used in animal models of dysfunctional coping, although active coping strategies are associated with generalized anxiety disorder, social anxiety disorder, panic, and phobias as well as obsessive-compulsive and post-traumatic stress disorder. This paper analyzes the development of dysfunctional active coping strategies of mice of the helplessness-resistant DBA/2J (D2) inbred strain, submitted to temporary reduction in food availability in an uncontrollable and unavoidable condition. The results indicate that food-restricted D2 mice developed a stereotyped form of food anticipatory activity and dysfunctional reactive coping in novel aversive contexts and acquired inflexible and perseverant escape strategies in novel stressful situations. The evaluation of FosB/DeltaFosB immunostaining in different brain areas of food-restricted D2 mice revealed a pattern of expression typically associated with behavioral sensitization to addictive drugs and compulsivity. These results support the conclusion that an active coping style represents an endophenotype of mental disturbances characterized by perseverant and inflexible behavior.

Early life adversity affecting the attachment bond alters ventral tegmental area transcriptomic patterning and behavior almost exclusively in female mice.

Early life experiences that affect the attachment bond formation can alter developmental trajectories and result in pathological outcomes in a sex-related manner. However, the molecular basis of sex differences is quite unknown. The dopaminergic system originating from the ventral tegmental area has been proposed to be a key mediator of this process. Here we exploited a murine model of early adversity (Repeated Cross Fostering, RCF) to test how interfering with the attachment bond formation affects the VTA-related functions in a sex-specific manner. Through a comprehensive behavioral screening, within the NiH RDoC framework, and by next-generation RNA-Seq experiments, we analyzed the long-lasting effect of RCF on behavioral and transcriptional profiles related to the VTA, across two different inbred strains of mouse in both sexes. We found that RCF impacted to an extremely greater extent VTA-related behaviors in females than in males and this result mirrored the transcriptional alterations in the VTA that were almost exclusively observed in females. The sexual dimorphism was conserved across two different inbred strains in spite of their divergent long lasting consequences of RCF exposure. Our data suggest that to be female primes a sub-set of genes to respond to early environmental perturbations. This is, to the best of our knowledge, the first evidence of an almost exclusive effect of early life experiences on females, thus mirroring the extremely stronger impact of precocious aversive events reported in clinical studies in women.

Intellectual Disability and Brain Creatine Deficit: Phenotyping of the Genetic Mouse Model for GAMT Deficiency.

Guanidinoacetate methyltransferase deficiency (GAMT-D) is one of three cerebral creatine (Cr) deficiency syndromes due to pathogenic variants in the GAMT gene (19p13.3). GAMT-D is characterized by the accumulation of guanidinoacetic acid (GAA) and the depletion of Cr, which result in severe global developmental delay (and intellectual disability), movement disorder, and epilepsy. The GAMT knockout (KO) mouse model presents biochemical alterations in bodily fluids, the brain, and muscles, including increased GAA and decreased Cr and creatinine (Crn) levels, which are similar to those observed in humans. At the behavioral level, only limited and mild alterations have been reported, with a large part of analyzed behaviors being unaffected in GAMT KO as compared with wild-type mice. At the cerebral level, decreased Cr and Crn and increased GAA and other guanidine compound levels have been observed. Nevertheless, the effects of Cr deficiency and GAA accumulation on many neurochemical, morphological, and molecular processes have not yet been explored. In this review, we summarize data regarding behavioral and cerebral GAMT KO phenotypes, and focus on uncharted behavioral alterations that are comparable with the clinical symptoms reported in GAMT-D patients, including intellectual disability, poor speech, and autistic-like behaviors, as well as unexplored Cr-induced cerebral alterations.

Opposite genotype-specific effects of serotoninergic treatments on Pavlovian Conditioned Approach in mice of two inbred strains C57 BL/6J and DBA/2J.

Individual variability in the response to pharmacological therapies is a major problem in the treatment of psychiatric disorders. Comparative studies of phenotypes expressed by mice of the C57BL/6J (C57) and DBA/2J (DBA) inbred strains can help identify neurobiological determinants of this variability at preclinical levels. We have recently demonstrated that whereas young adult mice of both strains develop sign-tracking in a Pavlovian Conditioned Approach (PCA), a trait associated with dysfunctional behavior in rat models, in full adult C57 mice acquisition of this phenotype is inhibited by pre-frontal cortical (PFC) serotonin (5HT) transmission. These findings suggest a different role of 5HT transmission on sign-tracking development in mice of the two genotypes. In the present experiments, we tested the effects of the 5-HT synthesis booster 5-hydroxytryptophan (5-HTP) and of the selective 5HT reuptake inhibitor (SSRI) fluoxetine on the development and expression of sign-tracking in young adult mice from both inbred strains. In mice of the C57 strain, administration of 5-HTP before each training session blocked the training-induced shift to positive PCA scores which indicates the development of sign-tracking, whereas the same treatment was ineffective in mice of DBA strain. On the other hand, a single administration of fluoxetine was ineffective in unhandled saline- and 5-HTP-treated C57 mice, whereas it enhanced the expression of positive PCA scores by mice of DBA strain treated with 5-HTP during training. These findings confirm the strain-specific inhibitory role of PFC 5-HT transmission on sign-tracking development by mice of the C57 strain and support the hypothesis that different genotype-specific neurobiological substrates of dysfunctional phenotypes contribute to variable effects of pharmacotherapies.

Interactions Between Experience, Genotype and Sex in the Development of Individual Coping Strategies.

Coping strategies, the first line of defense against adversities, develop through experience. There is consistent evidence that both genotype and sex contribute to the development of dysfunctional coping, leading to maladaptive outcomes of adverse experiences or to adaptive coping that fosters rapid recovery even from severe stress. However, how these factors interact to influence the development of individual coping strategies is just starting to be investigated. In the following review, we will consider evidence that experience, sex, and genotype influence the brain circuits and neurobiological processes involved in coping with adversities and discuss recent results pointing to the specific effects of the interaction between early experiences, genotype, and stress in the development of functional and dysfunctional coping styles.

RISC RNA sequencing in the Dorsal Raphè reveals microRNAs regulatory activities associated with behavioral and functional adaptations to chronic stress.

The Dorsal Raphe (DR) is the primary source of serotonergic input in the brain and a center for the homeostatic maintenance of the serotonergic tone. Under repeated stimulation, it can undergo adaptive modifications that alter serotonergic neurotransmission, which can lead to behavioral dysfunction. Post-transcriptional regulation by microRNAs is implicated in these adaptations. However, a global microRNA/target network effect on the DR neuroplasticity has yet to be elucidated. Here we investigate the microRNAs/mRNAs regulatory activity in the mouse DR after a chronic stress experience. First, we assessed the behavioral consequences of repeated restraint stress exposure and the functional adaptations of the DR by measuring the change in acute stress-induced serotonin release. Then, through next generation RNA-Seq of Argonaute2-bound RNA (RISC-Seq) we identified microRNAs and their targets that are associated to the RISC complex of the DR in unstressed and stressed mice. We mapped the potential microRNA/mRNA network within the stress-altered transcripts, uncovering new interactions that contribute to the chronic stress-induced DR modifications.

Functional and Dysfunctional Neuroplasticity in Learning to Cope with Stress.

In this brief review, we present evidence of the primary role of learning-associated plasticity in the development of either adaptive or maladaptive coping strategies. Successful interactions with novel stressors foster plasticity within the neural circuits supporting acquisition, consolidation, retrieval, and extinction of instrumental learning leading to development of a rich repertoire of flexible and context-specific adaptive coping responses, whereas prolonged or repeated exposure to inescapable/uncontrollable stressors fosters dysfunctional plasticity within the learning circuits leading to perseverant and inflexible maladaptive coping strategies. Finally, the results collected using an animal model of genotype-specific coping styles indicate the engagement of different molecular networks and the opposite direction of stress effects (reduced vs. enhanced gene expression) in stressed animals, as well as different behavioral alterations, in line with differences in the symptoms profile associated with post-traumatic stress disorder.

Genetic Up-Regulation or Pharmacological Activation of the Na+/Ca2+ Exchanger 1 (NCX1) Enhances Hippocampal-Dependent Contextual and Spatial Learning and Memory.

The Na+/Ca2+ exchanger 1 (NCX1) participates in the maintenance of neuronal Na+ and Ca2+ homeostasis, and it is highly expressed at synapse level of some brain areas involved in learning and memory processes, including the hippocampus, cortex, and amygdala. Furthermore, NCX1 increases Akt1 phosphorylation and enhances glutamate-mediated Ca2+ influx during depolarization in hippocampal and cortical neurons, two processes involved in learning and memory mechanisms. We investigated whether the modulation of NCX1 expression/activity might influence learning and memory processes. To this aim, we used a knock-in mouse overexpressing NCX1 in hippocampal, cortical, and amygdala neurons (ncx1.4over) and a newly synthesized selective NCX1 stimulating compound, named CN-PYB2. Both ncx1.4over and CN-PYB2-treated mice showed an amelioration in spatial learning performance in Barnes maze task, and in context-dependent memory consolidation after trace fear conditioning. On the other hand, these mice showed no improvement in novel object recognition task which is mainly dependent on non-spatial memory and displayed an increase in the active phosphorylated CaMKIIα levels in the hippocampus. Interestingly, both of these mice showed an increased level of context-dependent anxiety.Altogether, these results demonstrate that neuronal NCX1 participates in spatial-dependent hippocampal learning and memory processes.

Animal models of liability to post-traumatic stress disorder: going beyond fear memory.

In this review, we advocate a dimensional approach on the basis of candidate endophenotypes to the development of animal models of post-traumatic stress disorder (PTSD) capable of including genetic liability factors, variations in symptoms profile and underlying neurobiological mechanisms, and specific comorbidities. Results from the clinical literature pointed to two candidate endophenotypes of PTSD: low sensory gating and high waiting impulsivity. Findings of comparative studies in mice of two inbred strains characterized by different expressions of the two candidate endophenotypes showed different strain-specific neural and behavioral effects of stress experiences. Thus, mice of the standard C57BL/6J strain show stress-induced helplessness, stress-learned helplessness, and stress-extinction-resistant conditioned freezing. Instead, mice of the genetically unrelated DBA/2J strain, expressing both candidate endophenotypes, show stress-induced extinction-resistant avoidance and neural and behavioral phenotypes promoted by prolonged exposure to addictive drugs. These strain differences are in line with evidence of associations between genetic variants and specific stress-promoted pathological profiles in PTSD, support a role of genotype in determining different PTSD comorbidities, and offer the means to investigate specific pathogenic processes.

A new therapy prevents intellectual disability in mouse with phenylketonuria.

Untreated phenylketonuria (PKU) results in severe neurodevelopmental disorders, which can be partially prevented by an early and rigorous limitation of phenylalanine (Phe) intake. Enzyme substitution therapy with recombinant Anabaena variabilis Phe Ammonia Lyase (rAvPAL) proved to be effective in reducing blood Phe levels in preclinical and clinical studies of adults with PKU. Aims of present study were: a) to gather proofs of clinical efficacy of rAvPAL treatment in preventing neurological impairment in an early treated murine model of PKU; b) to test the advantages of an alternative delivering system for rAvPAL such as autologous erythrocytes. BTBR-Pahenu2-/- mice were treated from 15 to 64 post-natal days with weekly infusions of erythrocytes loaded with rAvPAL. Behavioral, neurochemical, and brain histological markers denoting untreated PKU were examined in early treated adult mice in comparison with untreated and wild type animals. rAvPAL therapy normalized blood and brain Phe; prevented cognitive developmental failure, brain depletion of serotonin, dendritic spine abnormalities, and myelin basic protein reduction. No adverse events or inactivating immune reaction were observed. In conclusion present study testifies the clinical efficacy of rAvPAL treatment in a preclinical model of PKU and the advantages of erythrocytes as carrier of the enzyme in term of frequency of the administrations and prevention of immunological reactions.

Norepinephrine in the Medial Pre-frontal Cortex Supports Accumbens Shell Responses to a Novel Palatable Food in Food-Restricted Mice Only.

Previous findings from this laboratory demonstrate: (1) that different classes of addictive drugs require intact norepinephrine (NE) transmission in the medial pre Frontal Cortex (mpFC) to promote conditioned place preference and to increase dopamine (DA) tone in the nucleus accumbens shell (NAc Shell); (2) that only food-restricted mice require intact NE transmission in the mpFC to develop conditioned preference for a context associated with milk chocolate; and (3) that food-restricted mice show a significantly larger increase of mpFC NE outflow then free fed mice when experiencing the palatable food for the first time. In the present study we tested the hypothesis that only the high levels of frontal cortical NE elicited by the natural reward in food restricted mice stimulate mesoaccumbens DA transmission. To this aim we investigated the ability of a first experience with milk chocolate to increase DA outflow in the accumbens Shell and c-fos expression in striatal and limbic areas of food-restricted and ad-libitum fed mice. Moreover, we tested the effects of a selective depletion of frontal cortical NE on both responses in either feeding group. Only in food-restricted mice milk chocolate induced an increase of DA outflow beyond baseline in the accumbens Shell and a c-fos expression larger than that promoted by a novel inedible object in the nucleus accumbens. Moreover, depletion of frontal cortical NE selectively prevented both the increase of DA outflow and the large expression of c-fos promoted by milk chocolate in the NAc Shell of food-restricted mice. These findings support the conclusion that in food-restricted mice a novel palatable food activates the motivational circuit engaged by addictive drugs and support the development of noradrenergic pharmacology of motivational disturbances.

Stress-Induced Reduction of Dorsal Striatal D2 Dopamine Receptors Prevents Retention of a Newly Acquired Adaptive Coping Strategy.

The inability to learn an adaptive coping strategy in a novel stressful condition leads to dysfunctional stress coping, a marker of mental disturbances. This study tested the involvement of dorsal striatal dopamine receptors in the dysfunctional coping with the Forced Swim test fostered by a previous experience of reduced food availability. Adult male mice were submitted to a temporary (12 days) reduction of food availability [food-restricted (FR)] or continuously free-fed (FF). Different groups of FF and FR mice were used to evaluate: (1) dorsal striatal mRNA levels of the two isoforms of the dopamine D2 receptor (D2S, D2L). (2) Forced Swim-induced c-fos expression in the dorsal striatum; (3) acquisition and 24 h retention of passive coping with Forced Swim. Additional groups of FF mice were tested for 24 h retention of passive coping acquired during a first experience with Forced Swim immediately followed by intra-striatal infusion of vehicle or two doses of the dopamine D2/D3 receptors antagonist sulpiride or the D1/D5 receptors antagonist SCH23390. Previous restricted feeding selectively reduced mRNA levels of both D2 isoforms and abolished Forced Swim-induced c-fos expression in the left Dorsolateral Striatum and selectively prevented 24 h retention of the coping strategy acquired in a first experience of Forced Swim. Finally, temporary blockade of left Dorsolateral Striatum D2/D3 receptors immediately following the first Forced Swim experience selectively reproduced the behavioral effect of restricted feeding in FF mice. In conclusion, the present results demonstrate that mice previously exposed to a temporary reduction of food availability show low striatal D2 receptors, a known marker of addiction-associated aberrant neuroplasticity, as well as liability to relapse into maladaptive stress coping strategies. Moreover, they offer strong support to a causal relationship between reduction of D2 receptors in the left Dorsolateral Striatum and impaired consolidation of newly acquired adaptive coping.

Fatigue modulates dopamine availability and promotes flexible choice reversals during decision making.

During decisions, animals balance goal achievement and effort management. Despite physical exercise and fatigue significantly affecting the levels of effort that an animal exerts to obtain a reward, their role in effort-based choice and the underlying neurochemistry are incompletely known. In particular, it is unclear whether fatigue influences decision (cost-benefit) strategies flexibly or only post-decision action execution and learning. To answer this question, we trained mice on a T-maze task in which they chose between a high-cost, high-reward arm (HR), which included a barrier, and a low-cost, low-reward arm (LR), with no barrier. The animals were parametrically fatigued immediately before the behavioural tasks by running on a treadmill. We report a sharp choice reversal, from the HR to LR arm, at 80% of their peak workload (PW), which was temporary and specific, as the mice returned to choose the HC when the animals were successively tested at 60% PW or in a two-barrier task. These rapid reversals are signatures of flexible choice. We also observed increased subcortical dopamine levels in fatigued mice: a marker of individual bias to use model-based control in humans. Our results indicate that fatigue levels can be incorporated in flexible cost-benefits computations that improve foraging efficiency.

The Relationship Between Specific Pavlovian Instrumental Transfer and Instrumental Reward Probability.

Goal-directed behavior is influenced by environmental cues: in particular, cues associated with a reward can bias action choice toward actions directed to that same reward. This effect is studied experimentally as specific Pavlovian-instrumental transfer (specific PIT). We have investigated the hypothesis that cues associated to an outcome elicit specific PIT by rising the estimates of reward probability of actions associated to that same outcome. In other words, cues reduce the uncertainty on the efficacy of instrumental actions. We used a human PIT experimental paradigm to test the effects of two different instrumental contingencies: one group of participants had a 33% chance of being rewarded for each button press, while another had a 100% chance. The group trained with 33% reward probability showed a stronger PIT effect than the 100% group, in line with the hypothesis that Pavlovian cues linked to an outcome work by reducing the uncertainty of receiving it. The 100% group also showed a significant specific PIT effect, highlighting additional factors that could contribute to specific PIT beyond the instrumental training contingency. We hypothesize that the uncertainty about reward delivery due to testing in extinction might be one of these factors. These results add knowledge on how goal-directed behavior is influenced by the presence of environmental cues associated with a reward: such influence depends on the probability that we have to reach a reward, namely when there is less chance of getting a reward we are more influenced by cues associated with it, and vice versa.

Corticolimbic catecholamines in stress: a computational model of the appraisal of controllability.

Appraisal of a stressful situation and the possibility to control or avoid it is thought to involve frontal-cortical mechanisms. The precise mechanism underlying this appraisal and its translation into effective stress coping (the regulation of physiological and behavioural responses) are poorly understood. Here, we propose a computational model which involves tuning motivational arousal to the appraised stressing condition. The model provides a causal explanation of the shift from active to passive coping strategies, i.e. from a condition characterised by high motivational arousal, required to deal with a situation appraised as stressful, to a condition characterised by emotional and motivational withdrawal, required when the stressful situation is appraised as uncontrollable/unavoidable. The model is motivated by results acquired via microdialysis recordings in rats and highlights the presence of two competing circuits dominated by different areas of the ventromedial prefrontal cortex: these are shown having opposite effects on several subcortical areas, affecting dopamine outflow in the striatum, and therefore controlling motivation. We start by reviewing published data supporting structure and functioning of the neural model and present the computational model itself with its essential neural mechanisms. Finally, we show the results of a new experiment, involving the condition of repeated inescapable stress, which validate most of the model's predictions.