Predictive and motivational factors influencing anticipatory contrast: A comparison of contextual and gustatory predictors in food restricted and free-fed rats

In anticipation of palatable food, rats can learn to restrict consumption of a less rewarding food type resulting in an increased consumption of the preferred food when it is made available. This construct is known as anticipatory negative contrast (ANC) and can help elucidate the processes that underlie binge-like behavior as well as self-control in rodent motivation models. In the current investigation we aimed to shed light on the ability of distinct predictors of a preferred food choice to generate contrast effects and the motivational processes that underlie this behavior. Using a novel set of rewarding solutions, we directly compared contextual and gustatory ANC predictors in both food restricted and free-fed Sprague-Dawley rats. Our results indicate that, despite being food restricted, rats are selective in their eating behavior and show strong contextually-driven ANC similar to free-fed animals. These differences mirrored changes in palatability for the less preferred solution across the different sessions as measured by lick microstructure analysis. In contrast to previous research, predictive cues in both food restricted and free-fed rats were sufficient for ANC to develop although flavor-driven ANC did not relate to a corresponding change in lick patterning. These differences in the lick microstructure between context- and flavor-driven ANC indicate that the motivational processes underlying ANC generated by the two predictor types are distinct. Moreover, an increase in premature port entries to the unavailable sipper – a second measure of ANC – in all groups reveals a direct influence of response competition on ANC development

Neuropeptide S Encodes Stimulus Salience in the Paraventricular Thalamus

Evaluation of stimulus salience is critical for any higher organism, as it allows for prioritizing of vital information, preparation of responses, and formation of valuable memory. The paraventricular nucleus of the thalamus (PVT) has recently been identified as an integrator of stimulus salience but the neurochemical basis and afferent input regarding salience signaling have remained elusive. Here we report that neuropeptide S (NPS) signaling in the PVT is necessary for stimulus salience encoding, including aversive, neutral and reinforcing sensory input. Taking advantage of a striking deficit of both NPS receptor (NPSR1) and NPS precursor knockout mice in fear extinction or novel object memory formation, we demonstrate that intra-PVT injections of NPS can rescue the phenotype in NPS precursor knockout mice by increasing the salience of otherwise low-intensity stimuli, while intra-PVT injections of NPSR1 antagonist in wild type mice partially replicates the knockout phenotype. The PVT appears to provide stimulus salience encoding in a dose- and NPS-dependent manner. PVT NPSR1 neurons recruit the nucleus accumbens shell and structures in the prefrontal cortex and amygdala, which were previously linked to the brain salience network. Overall, these results demonstrate that stimulus salience encoding is critically associated with NPS activity in the PVT

Melanin concentrating hormone modulates oxytocin-mediated marble burying

Repetitive and perseverative behaviors are common features of a number of neuropsychiatric diseases such as Angelman's syndrome, Tourette's syndrome, obsessive-compulsive disorder, and autism spectrum disorders. The oxytocin system has been linked to the regulation of repetitive behavior in both animal models and humans, but many of its downstream targets have still to be found. We report that the melanin-concentrating hormone (MCH) system is a target of the oxytocin system in regulating one repetitive behavior, marble burying. First we report that nearly 60% of MCH neurons express oxytocin receptors, and demonstrate using rabies mediated tract tracing that MCH neurons receive direct presynaptic input from oxytocin neurons. Then we show that MCH receptor knockout (MCHR1KO) mice and MCH ablated animals display increased marble burying response while central MCH infusion decreases it. Finally, we demonstrate the downstream role of the MCH system on oxytocin mediated marble burying by showing that central infusions of MCH and oxytocin alone or together reduce it while antagonizing the MCH system blocks oxytocin-mediated reduction of this behavior. Our findings reveal a novel role for the MCH system as a mediator of the role of oxytocin in regulating marble-burying behavior in mice

Melanin concentrating hormone modulates oxytocin-mediated marble burying.

Repetitive and perseverative behaviors are common features of a number of neuropsychiatric diseases such as Angelman's syndrome, Tourette's syndrome, obsessive-compulsive disorder, and autism spectrum disorders. The oxytocin system has been linked to the regulation of repetitive behavior in both animal models and humans, but many of its downstream targets have still to be found. We report that the melanin-concentrating hormone (MCH) system is a target of the oxytocin system in regulating one repetitive behavior, marble burying. First we report that nearly 60% of MCH neurons express oxytocin receptors, and demonstrate using rabies mediated tract tracing that MCH neurons receive direct presynaptic input from oxytocin neurons. Then we show that MCH receptor knockout (MCHR1KO) mice and MCH ablated animals display increased marble burying response while central MCH infusion decreases it. Finally, we demonstrate the downstream role of the MCH system on oxytocin mediated marble burying by showing that central infusions of MCH and oxytocin alone or together reduce it while antagonizing the MCH system blocks oxytocin-mediated reduction of this behavior. Our findings reveal a novel role for the MCH system as a mediator of the role of oxytocin in regulating marble-burying behavior in mice

Sex differences in the antidepressant-like response and molecular events induced by the imidazoline-2 receptor agonist CR4056 in rats

In searching for novel targets to design antidepressants, among the characterized imidazoline receptors (IR), I2 receptors are an innovative therapeutical approach since they are dysregulated in major depressive disorder and by classical antidepressant treatments. In fact, several I2 agonists have been characterized for their antidepressant-like potential, but the results in terms of efficacy were mixed and exclusively reported in male rodents. Since there are well-known sex differences in antidepressant-like efficacy, this study characterized the potential effects induced by two I2 drugs, CR4056 (i.e., most promising drug already in phase II clinical trial for its analgesic properties) and B06 (a compound from a new family of bicyclic α-iminophosphonates) under the stress of the forced-swim test in male and female rats exposed to early-life stress. Moreover, some hippocampal neuroplasticity markers related to the potential effects observed were also evaluated (i.e., FADD, p-ERK/ERK, mBDNF, cell proliferation: Ki-67 + cells). The main results replicated the only prior study reporting the efficacy of CR4056 in male rats, while providing new data on its efficacy in females, which was clearly dependent on prior early-life stress exposure. Moreover, B06 showed no antidepressant-like effects in male or female rats. Finally, CR4056 increased FADD content and decreased cell proliferation in hippocampus, without affecting p- ERK/t-ERK ratio and/or mBDNF content. Interestingly, these effects were exclusively observed in female rats, and independently of early-life conditions, suggesting some distinctive molecular underpinnings participating in the therapeutic response of CR4056 for both sexes. In conjunction, these results present CR4056 with an antidepressant-like potential, especially in female rats exposed to stress early in life, together with some neuronal correlates described in the context of these behavioral changes in females

Chronic melatonin treatment and its precursor L-tryptophan improve the monoaminergic neurotransmission and related behavior in the aged rat brain

[eng] Abstract: Melatonin has an important role in the aging process as a potential drug to relieve oxidative damage, a likely cause of age-associated brain dysfunction. As age advances, the nocturnal production of melatonin decreases potentially causing physiological alterations. The present experiments were performed to study in vivo the effects of exogenously administered melatonin chronically on monoaminergic central neurotransmitters serotonin (5-HT), dopamine (DA) and norepinephrine (NE) and behavioral tests in old rats. The accumulation of 5-hydroxytryptophan (5-HTP) and L-3,4-dihydroxyphenylalanine (DOPA) after decarboxylase inhibition was used as a measure of the rate of tryptophan and tyrosine hydroxylation in rat brain. Also neurotransmitters 5-HT, DA and NE and some metabolites were quantified by HPLC. In control rats, an agerelated decline was observed in neurochemical parameters. However, chronic administration of melatonin (1 mg/kg/day, diluted in drinking water, 4 wk) significantly reversed the age-induced deficits in all the monoaminergic neurotransmitters studied. Also, neurochemical parameters were analyzed after administration of melatonin biosynthesis precursor L-tryptophan (240 mg/kg/day, i.p., at night for 4 wk) revealing similar improvement effects to those induced by melatonin. Behavioral data corresponded well with the neurochemical findings since spatial memory test in radial-maze and motor coordination in rota-rod were significantly improved after chronic melatonin treatment. In conclusion, these in vivo findings suggest that melatonin and L-tryptophan treatments exert a long-term effect on the 5-HT, DA and NE neurotransmission by enhancing monoamine synthesis in aged rats, which might improve the age-dependent deficits in cognition and motor coordination

Improving effects of long-term growth hormone treatment on monoaminergic neurotransmission and related behavioral tests in aged rats

[eng] An age-related decline in cognitive functions and physical performance has been associated with reductions in growth hormone (GH) secretion and brain neurotransmitter function. In vivo experiments were performed to study the long-term effects of exogenously administered GH on the central monoaminergic neurotransmitters serotonin, dopamine, and noradrenaline and behavioral tests in old Wistar rats. The accumulation of 5-hydroxytryptophan (5-HTP) and L-3,4-dihydroxyphenylalanine (DOPA) after decarboxylase inhibition was used as a measure of the rate of tryptophan and tyrosine hydroxylation in vivo. Also, the content of the neurotransmitters serotonin, dopamine, and noradrenaline and some metabolites was measured by high-pressure liquid chromatography (HPLC) in the hippocampus and striatum, brain regions involved in adult memory processing and motor coordination. The age-related decline observed in all the neurochemical parameters in control rats was significantly reversed after repeated subcutaneous administration of GH (2mg/kg per day, 4 weeks). Thus, GH treatment exerted a long-term effect on serotonin, dopamine, and noradrenaline neurotransmission by enhancing neurotransmitter synthesis and metabolism in aged rats. The results obtained after examining working memory tasks in the eight-radial maze and motor ability in the Rotarod treadmill in aged rats were consistent with these neurochemical data; both tests were significantly improved after chronic GH treatment. Overall, these in vivo findings suggest that the positive effects induced by GH on serotonin, dopamine, and noradrenaline neurotransmitters might explain, at least in part, the effects of chronic GH treatment in improving cognitive and motor ability in aged rats, and could aid in preventing or delaying deficits in monoamines associated with learning or motor disabilities