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

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 prediction

A computational model of stress coping in rats

No abstract availabl

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

none9noGuanidinoacetate 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.openRossi, Luigia; Nardecchia, Francesca; Pierigè, Francesca; Ventura, Rossella; Carducci, Claudia; Leuzzi, Vincenzo; Magnani, Mauro; Cabib, Simona; Pascucci, TizianaRossi, Luigia; Nardecchia, Francesca; Pierigè, Francesca; Ventura, Rossella; Carducci, Claudia; Leuzzi, Vincenzo; Magnani, Mauro; Cabib, Simona; Pascucci, Tizian

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

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\u27s predictions

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

Barrel pattern formation requires serotonin uptake by thalamocortical afferents, and not vesicular monoamine release

Thalamocortical neurons innervating the barrel cortex in neonatal rodents transiently store serotonin (5-HT) in synaptic vesicles by expressing the plasma membrane serotonin transporter (5-HTT) and the vesicular monoamine transporter (VMAT2). 5-HTT knock-out (ko) mice reveal a nearly complete absence of 5-HT in the cerebral cortex by immunohistochemistry, and of barrels, both at P7 and adulthood. Quantitative electron microscopy reveals that 5-HTT ko affects neither the density of synapses nor the length of synaptic contacts in layer IV. VMAT2 ko mice, completely lacking activity-dependent vesicular release of monoamines including 5-HT, also show a complete lack of 5-HT in the cortex but display largely normal barrel fields, despite sometimes markedly reduced postnatal growth. Transient 5-HTT expression is thus required for barrel pattern formation, whereas activity-dependent vesicular 5-HT release is not