Reward Enhances Memory via Age-Varying Online and Offline Neural Mechanisms across Development.

Reward motivation enhances memory through interactions between mesolimbic, hippocampal, and cortical systems, both during and after encoding. Developmental changes in these distributed neural circuits may lead to age-related differences in reward-motivated memory and the underlying neural mechanisms. Converging evidence from cross-species studies suggests that subcortical dopamine signaling is increased during adolescence, which may lead to stronger memory representations of rewarding, relative to mundane, events and changes in the contributions of underlying subcortical and cortical brain mechanisms across age. Here, we used fMRI to examine how reward motivation influences the "online" encoding and "offline" postencoding brain mechanisms that support long-term associative memory from childhood to adulthood in human participants of both sexes. We found that reward motivation led to both age-invariant enhancements and nonlinear age-related differences in associative memory after 24 h. Furthermore, reward-related memory benefits were linked to age-varying neural mechanisms. During encoding, interactions between the prefrontal cortex (PFC) and ventral tegmental area (VTA) were associated with better high-reward memory to a greater degree with increasing age. Preencoding to postencoding changes in functional connectivity between the anterior hippocampus and VTA were also associated with better high-reward memory, but more so at younger ages. Our findings suggest that there may be developmental differences in the contributions of offline subcortical and online cortical brain mechanisms supporting reward-motivated memory.SIGNIFICANCE STATEMENT A substantial body of research has examined the neural mechanisms through which reward influences memory formation in adults. However, despite extensive evidence that both reward processing and associative memory undergo dynamic change across development, few studies have examined age-related changes in these processes. We found both age-invariant and nonlinear age-related differences in reward-motivated memory. Moreover, our findings point to developmental differences in the processes through which reward modulates the prioritization of information in long-term memory, with greater early reliance on offline subcortical consolidation mechanisms and increased contribution of systems-level online encoding circuitry with increasing age. These results highlight dynamic developmental changes in the cognitive and neural mechanisms through which motivationally salient information is prioritized in memory from childhood to adulthood.

Chronic Voluntary Alcohol Consumption Alters Promoter Methylation and Expression of Fgf-2 and Fgfr1.

Alcohol abuse accounts for 3.3 million deaths annually, rendering it a global health issue. Recently, fibroblast growth factor 2 (FGF-2) and its target, fibroblast growth factor receptor 1 (FGFR1), were discovered to positively regulate alcohol-drinking behaviors in mice. We tested whether alcohol intake and withdrawal alter DNA methylation of Fgf-2 and Fgfr1 and if there is a correlation regarding mRNA expression of these genes. Blood and brain tissues of mice receiving alcohol intermittently over a six-week period were analyzed using direct bisulfite sequencing and qRT-PCR analysis. Assessment of Fgf-2 and Fgfr1 promoter methylation revealed changes in the methylation of cytosines in the alcohol group compared with the control group. Moreover, we showed that the altered cytosines coincided with binding motives of several transcription factors. We also found that Fgf-2 and Fgfr1 gene expression was significantly decreased in alcohol-receiving mice compared with control littermates, and that this effect was specifically detected in the dorsomedial striatum, a brain region involved in the circuitry of the reward system. Overall, our data showed alcohol-induced alterations in both mRNA expression and methylation pattern of Fgf-2 and Fgfr1. Furthermore, these alterations showed a reward system regional specificity, therefore, resembling potential targets for future pharmacological interventions.

Subthalamic nucleus deep brain stimulation induces sustained neurorestoration in the mesolimbic dopaminergic system in a Parkinson's disease model.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established therapeutic principle in Parkinson's disease, but the underlying mechanisms, particularly mediating non-motor actions, remain largely enigmatic. OBJECTIVE/HYPOTHESIS: The delayed onset of neuropsychiatric actions in conjunction with first experimental evidence that STN-DBS causes disease-modifying effects prompted our investigation on how cellular plasticity in midbrain dopaminergic systems is affected by STN-DBS. METHODS: We applied unilateral or bilateral STN-DBS in two independent cohorts of 6-hydroxydopamine hemiparkinsonian rats four to eight weeks after dopaminergic lesioning to allow for the development of a stable dopaminergic dysfunction prior to DBS electrode implantation. RESULTS: After 5 weeks of STN-DBS, stimulated animals had significantly more TH+ dopaminergic neurons and fibres in both the nigrostriatal and the mesolimbic systems compared to sham controls with large effect sizes of gHedges = 1.9-3.4. DBS of the entopeduncular nucleus as the homologue of the human Globus pallidus internus did not alter the dopaminergic systems. STN-DBS effects on mesolimbic dopaminergic neurons were largely confirmed in an independent animal cohort with unilateral STN stimulation for 6 weeks or for 3 weeks followed by a 3 weeks washout period. The latter subgroup even demonstrated persistent mesolimbic dopaminergic plasticity after washout. Pilot behavioural testing showed that augmentative dopaminergic effects on the mesolimbic system by STN-DBS might translate into improvement of sensorimotor neglect. CONCLUSIONS: Our data support sustained neurorestorative effects of STN-DBS not only in the nigrostriatal but also in the mesolimbic system as a potential factor mediating long-latency neuropsychiatric effects of STN-DBS in Parkinson's disease.

The Brain's Reward System in Health and Disease.

Rhythmic gene expression is found throughout the central nervous system. This harmonized regulation can be dependent on- and independent of- the master regulator of biological clocks, the suprachiasmatic nucleus (SCN). Substantial oscillatory activity in the brain's reward system is regulated by dopamine. While light serves as a primary time-giver (zeitgeber) of physiological clocks and synchronizes biological rhythms in 24-h cycles, nonphotic stimuli have a profound influence over circadian biology. Indeed, reward-related activities (e.g., feeding, exercise, sex, substance use, and social interactions), which lead to an elevated level of dopamine, alters rhythms in the SCN and the brain's reward system. In this chapter, we will discuss the influence of the dopaminergic reward pathways on circadian system and the implication of this interplay on human health.

Orexin-A up-regulates dopamine D2 receptor and mRNA in the nucleus accumbens Shell.

Orexins-A (OrxA) and -B (OrxB) neuropeptides are synthesized by a group of neurons located in the lateral hypothalamus and adjacent perifornical area, which send their projections to the mesolimbic dopaminergic (DAergic) system including ventral tegmental area and nucleus accumbens (NAc), where orexin receptors are expressed. NAc plays a central role in reward-seeking behavior and drug abuse. NAc-neurons express dopamine-1 (D1R) and dopamine-2 (D2R) receptors. Orexins bind to their two cognate G-protein-coupled receptors, orexin-receptor type-1 (Orx1R) and type-2 (Orx2R). Orexin receptor signaling is involved in behaviors such as motivation and addiction. Orexin-containing neurons modulate DAergic activity that is key in synaptic plasticity induced by addictive drugs. However, the effect of OrxA on expression and content of DAergic receptors in NAc is unknown. The purpose of this study was to investigate whether OrxA can alter gene expression and protein levels of D1R/D2R in NAc. Gene expression was evaluated by real-time PCR analysis and protein levels by western blot in rats. The results show that intracerebroventricular (i.c.v.) injection of OrxA increases both gene transcription and protein content of D2R but fails to modify D1R. This effect was also confirmed with OrxA infusion in NAc/Shell. Our results demonstrate for the first time that OrxA induces up-regulation of gene and protein of D2R in NAc. These findings support the hypothesis that OrxA modulates the DAergic transmission and this may serve to understand how orexin signaling enhances DA responses at baseline conditions and in response to psychostimulants.

Retrieval Demands Adaptively Change Striatal Old/New Signals and Boost Subsequent Long-Term Memory.

The striatum is a central part of the dopaminergic mesolimbic system and contributes both to the encoding and retrieval of long-term memories. In this regard, the co-occurrence of striatal novelty and retrieval success effects in independent studies underlines the structure's double duty and suggests dynamic contextual adaptation. To test this hypothesis and further investigate the underlying mechanisms of encoding and retrieval dynamics, human subjects viewed pre-familiarized scene images intermixed with new scenes and classified them as indoor versus outdoor (encoding task) or old versus new (retrieval task), while fMRI and eye tracking data were recorded. Subsequently, subjects performed a final recognition task. As hypothesized, striatal activity and pupil size reflected task-conditional salience of old and new stimuli, but, unexpectedly, this effect was not reflected in the substantia nigra and ventral tegmental area (SN/VTA), medial temporal lobe, or subsequent memory performance. Instead, subsequent memory generally benefitted from retrieval, an effect possibly driven by task difficulty and activity in a network including different parts of the striatum and SN/VTA. Our findings extend memory models of encoding and retrieval dynamics by pinpointing a specific contextual factor that differentially modulates the functional properties of the mesolimbic system.SIGNIFICANCE STATEMENT The mesolimbic system is involved in the encoding and retrieval of information but it is unclear how these two processes are achieved within the same network of brain regions. In particular, memory retrieval and novelty encoding were considered in independent studies, implying that novelty (new > old) and retrieval success (old > new) effects may co-occur in the striatum. Here, we used a common framework implicating the striatum, but not other parts of the mesolimbic system, in tracking context-dependent salience of old and new information. The current study, therefore, paves the way for a more comprehensive understanding of the functional properties of the mesolimbic system during memory encoding and retrieval.

GDNF and alcohol use disorder.

Glial cell line-derived neurotrophic factor (GDNF) has been extensively studied for its role in the development and maintenance of the midbrain dopaminergic system, although evidence suggests that GDNF also plays a role in drug and alcohol addiction. This review focuses on the unique actions of GDNF in the mechanisms that prevent the transition from recreational alcohol use to abuse. Specifically, we describe studies in rodents suggesting that alcohol acutely increases GDNF expression in the ventral tegmental area, which enables the activation of the mitogen-activated protein kinase signaling pathway and the gating of alcohol intake. We further provide evidence to suggest that GDNF acts in the ventral tegmental area via both nongenomic and genomic mechanisms to suppress alcohol consumption. In addition, we describe findings indicating that when this endogenous protective pathway becomes dysregulated, alcohol intake levels escalate. Finally, we describe the potential use of GDNF inducers as a novel therapeutic approach to treat alcohol use disorder.

The Mechanisms Involved in Morphine Addiction: An Overview.

Opioid use disorder is classified as a chronic recurrent disease of the central nervous system (CNS) which leads to personality disorders, co-morbidities and premature death. It develops as a result of long-term administration of various abused substances, along with morphine. The pharmacological action of morphine is associated with its stimulation of opioid receptors. Opioid receptors are a group of G protein-coupled receptors and activation of these receptors by ligands induces significant molecular changes inside the cell, such as an inhibition of adenylate cyclase activity, activation of potassium channels and reductions of calcium conductance. Recent data indicate that other signalling pathways also may be involved in morphine activity. Among these are phospholipase C, mitogen-activated kinases (MAP kinases) or ß-arrestin. The present review focuses on major mechanisms which currently are considered as essential in morphine activity and dependence and may be important for further studies.

Social defeat stress induces hyperalgesia and increases truncated BDNF isoforms in the nucleus accumbens regardless of the depressive-like behavior induction in mice.

Epidemiological studies have shown a close association between pain and depression. There is evidence showing this association as patients with depression show a high chronic pain prevalence and vice versa. Considering that social stress is critical for the development of depression in humans, we used a social defeat stress (SDS) model which induces depressive-like behavior in mice. In this model, mice are exposed to an aggressor mouse for ten days, suffering brief periods of agonistic contact and long periods of sensory contact. Some mice display social avoidance, a depressive-like behavior, and are considered susceptible, while some mice do not, and are considered resilient. Thus, we investigated the nociceptive behavior of mice submitted to SDS and the neuroplastic changes in dopaminergic mesolimbic system. Our results showed that the stressed mice (resilient and susceptible) presented a higher sensitivity to pain than the control mice in chemical and mechanical tests. We also verified that susceptible mice have higher Bdnf mRNA in the VTA compared to the resilient and control mice. The stressed mice had less mature BDNF and more truncated BDNF protein in the NAc compared with control mice. Although social stress may trigger the development of depression and hyperalgesia, these two conditions may manifest independently as social stress induced hyperalgesia even in mice that did not display depressive-like behavior. Also, increased Bdnf in the VTA seems to be associated with depressive-like behavior, whereas high levels of truncated BDNF and low mature BDNF appear to be associated with hyperalgesia induced by social defeat stress.

Cannabidiol Counteracts Amphetamine-Induced Neuronal and Behavioral Sensitization of the Mesolimbic Dopamine Pathway through a Novel mTOR/p70S6 Kinase Signaling Pathway.

UNLABELLED: Schizophrenia-related psychosis is associated with disturbances in mesolimbic dopamine (DA) transmission, characterized by hyperdopaminergic activity in the mesolimbic pathway. Currently, the only clinically effective treatment for schizophrenia involves the use of antipsychotic medications that block DA receptor transmission. However, these medications produce serious side effects leading to poor compliance and treatment outcomes. Emerging evidence points to the involvement of a specific phytochemical component of marijuana called cannabidiol (CBD), which possesses promising therapeutic properties for the treatment of schizophrenia-related psychoses. However, the neuronal and molecular mechanisms through which CBD may exert these effects are entirely unknown. We used amphetamine (AMPH)-induced sensitization and sensorimotor gating in rats, two preclinical procedures relevant to schizophrenia-related psychopathology, combined with in vivo single-unit neuronal electrophysiology recordings in the ventral tegmental area, and molecular analyses to characterize the actions of CBD directly in the nucleus accumbens shell (NASh), a brain region that is the current target of most effective antipsychotics. We demonstrate that Intra-NASh CBD attenuates AMPH-induced sensitization, both in terms of DAergic neuronal activity measured in the ventral tegmental area and psychotomimetic behavioral analyses. We further report that CBD controls downstream phosphorylation of the mTOR/p70S6 kinase signaling pathways directly within the NASh. Our findings demonstrate a novel mechanism for the putative antipsychotic-like properties of CBD in the mesolimbic circuitry. We identify the molecular signaling pathways through which CBD may functionally reduce schizophrenia-like neuropsychopathology. SIGNIFICANCE STATEMENT: The cannabis-derived phytochemical, cannabidiol (CBD), has been shown to have pharmacotherapeutic efficacy for the treatment of schizophrenia. However, the mechanisms by which CBD may produce antipsychotic effects are entirely unknown. Using preclinical behavioral procedures combined with molecular analyses and in vivo neuronal electrophysiology, our findings identify a functional role for the nucleus accumbens as a critical brain region whereby CBD can produce effects similar to antipsychotic medications by triggering molecular signaling pathways associated with the effects of classic antipsychotic medications. Specifically, we report that CBD can attenuate both behavioral and dopaminergic neuronal correlates of mesolimbic dopaminergic sensitization, via a direct interaction with mTOR/p70S6 kinase signaling within the mesolimbic pathway.

Dopaminergic activation anticipates daily nursing in the rabbit.

Maternal care is a motivated behavior and in the rabbit it is restricted to the spontaneous return of the mother to nurse her pups for just a few minutes once a day. Previously we have reported neural activation of brain areas and neuroendocrine cells after nursing. However, this daily spontaneous return suggests that the mother is in a high motivational state to nurse her pups. Here we hypothesized that during anticipation of nursing there is an activation of dopaminergic neurons of the mesolimbic system and in their target areas. Then we explored, by the expression of FOS protein, possible activation of the mesolimbic system as well as dopaminergic cells of the A10 cell group before and after nursing and in control does. Additionally, we measured FOS expression in the preoptic area and lateral septum. We found a significant increase of FOS before nursing, and a further increase after nursing, in the mesolimbic system and dopaminergic cells as well as in the preoptic area and lateral septum. Interestingly, the medial prefrontal area shows an intense activation during anticipation of nursing, which remains after nursing. We conclude that the activation of the mesolimbic system before nursing is related to the high locomotor behavior prior to the next nursing bout and support the proposal that the mother is in a high motivational state at the time of returning to the nest. The additional activation after nursing can be related to the neuroendocrine and neural consequences of the milk ejection reflex by suckling.

Glucose modulates food-related salience coding of midbrain neurons in humans.

Although early rat studies demonstrated that administration of glucose diminishes dopaminergic midbrain activity, evidence in humans has been lacking so far. In the present functional magnetic resonance imaging study, glucose was intravenously infused in healthy human male participants while seeing images depicting low-caloric food (LC), high-caloric food (HC), and non-food (NF) during a food/NF discrimination task. Analysis of brain activation focused on the ventral tegmental area (VTA) as the origin of the mesolimbic system involved in salience coding. Under unmodulated fasting baseline conditions, VTA activation was greater during HC compared with LC food cues. Subsequent to infusion of glucose, this difference in VTA activation as a function of caloric load leveled off and even reversed. In a control group not receiving glucose, VTA activation during HC relative to LC cues remained stable throughout the course of the experiment. Similar treatment-specific patterns of brain activation were observed for the hypothalamus. The present findings show for the first time in humans that glucose infusion modulates salience coding mediated by the VTA. Hum Brain Mapp 37:4376-4384, 2016. © 2016 Wiley Periodicals, Inc.

Nucleus accumbens shell and core dopamine responsiveness to sucrose in rats: role of response contingency and discriminative/conditioned cues.

This study investigated by microdialysis the role of response contingency and food-associated cues in the responsiveness of dopamine transmission in the nucleus accumbens shell and core to sucrose feeding. In naive rats, single-trial non-contingent presentation and feeding of sucrose pellets increased dialysate shell dopamine and induced full habituation of dopamine responsiveness to sucrose feeding 24 and 48 h later. In rats trained to respond for sucrose pellets on a fixed ratio 1 (FR1) schedule, dialysate dopamine increased in the shell but not in the core during active responding as well as under extinction in the presence of sucrose cues. In rats yoked to the operant rats, the presentation of sucrose cues also increased dialysate dopamine selectively in the shell. In contrast, non-contingent sucrose presentation and feeding in FR1-trained and in yoked rats increased dialysate dopamine to a similar extent in the shell and core. It is concluded that, whereas non-contingent sucrose feeding activated dopamine transmission in the shell and core, response-contingent feeding activated, without habituation, dopamine transmission selectively in the shell as a result of the action of sucrose conditioned cues. These observations are consistent with a critical role of conditioned cues acquired during training and differential activation of shell vs. core dopamine for response-contingent sucrose feeding.

Pain anticipation recruits the mesolimbic system and differentially modulates subsequent recognition memory.

The ability to encode information into long-term memory is not a passive process but can be influenced by motivational factors. While the mesolimbic system has long been associated with reward-driven memory enhancement, the precise neurobiology of processing aversive events and their effects on declarative learning remain unclear. To address this issue, human subjects encoded a series of scene images, which was combined with cues predicting an aversive electric shock with different probabilities (0.2, 0.5, 0.8). Subsequently, recognition memory for the scenes was tested using a remember/know procedure. In a behavioral experiment, shock probability had linear effects on familiarity and inverted u-shaped effects on recollection. While the behavioral effect was absent in experiment 2 (fMRI), at the neural level encoding-related activity in the hippocampus mimicked the recollection specific quadratic effect, whereas activity in the anterior parahippocampal gyrus mirrored the familiarity specific linear relationship that was evident in experiment 1. Importantly, the probability of upcoming shocks was linearly coded in the substantia nigra / ventral tegmental area, and pain associated brain regions, such as the insula, responded to shock delivery. Our results demonstrate that anticipating primary aversive events recruits the human mesolimbic system and differentially modulates declarative memory functions via medial temporal lobe structures.

CRF release from a unique subpopulation of accumbal neurons constrains action-outcome acquisition in reward learning.

BACKGROUND: The nucleus accumbens (NAc) mediates reward learning and motivation. Despite an abundance of neuropeptides, peptidergic neurotransmission from the NAc has not been integrated into current models of reward learning. The existence of a sparse population of neurons containing corticotropin releasing factor (CRF) has been previously documented. Here we provide a comprehensive analysis of their identity and functional role in shaping reward learning. METHODS: To do this, we took a multidisciplinary approach that included florescent in situ hybridization (Nmice ≥ 3), tract tracing (Nmice = 5), ex vivo electrophysiology (Ncells ≥ 30), in vivo calcium imaging with fiber photometry (Nmice ≥ 4) and use of viral strategies in transgenic lines to selectively delete CRF peptide from NAc neurons (Nmice ≥ 4). Behaviors used were instrumental learning, sucrose preference and spontaneous exploration in an open field. RESULTS: Here we show that the vast majority of NAc CRF-containing (NAcCRF) neurons are spiny projection neurons (SPNs) comprised of dopamine D1-, D2- or D1/D2-containing SPNs that primarily project and connect to the ventral pallidum and to a lesser extent the ventral midbrain. As a population, they display mature and immature SPN firing properties. We demonstrate that NAcCRF neurons track reward outcomes during operant reward learning and that CRF release from these neurons acts to constrain initial acquisition of action-outcome learning, and at the same time facilitates flexibility in the face of changing contingencies. CONCLUSION: We conclude that CRF release from this sparse population of SPNs is critical for reward learning under normal conditions.

Asymmetric pain processing in Parkinson's disease.

BACKGROUND AND PURPOSE: Reduced endogenous pain inhibition, as part of the degenerative process, is presumed to be the mechanism underlying the common presence of pain in patients with Parkinson's disease (PD). The present study aimed to assess an endogenous pain inhibitory system in PD using the conditioned pain modulation paradigm. METHODS: Twenty-six predominantly unilateral PD patients and 19 controls underwent psychophysical pain assessment before and after patients' morning dopaminergic medication. RESULTS: An unexpected increase in several parameters of pain perception for PD patients was found after dopaminergic medication (e.g. for 49°C noxious heat stimulation an increase from 70.6 ± 4.0 to 77.6 ± 4.0 on the numerical pain scale, P < 0.001). This increase was seen in patients with predominantly left-sided PD, regardless of the stimulated side (for 49°C noxious heat stimulation, predominantly left-sided PD patients, pain perception increased from 73.5 ± 6.8 to 85.0 ± 6.8, P < 0.001, whereas predominantly right-sided PD patients did not show a significant increase, 68.3 ± 6.8 to 70.4 ± 6.5, P = 0.777). Baseline efficiency of conditioned pain modulation inversely correlated with age at disease onset (r = -0.522; P = 0.009) and disease severity (Unified PD Rating Scale, r = 0.447; P = 0.032) but did not differ between patients and controls. CONCLUSIONS: Increased sensory response causing hyperalgesia occurs after dopaminergic medication in patients with predominantly left-sided PD.

Activation of the central but not the medial and cortical amygdala during anticipation for daily nursing in the rabbit.

Rabbits have remarkable nursing behavior: after parturition, does visit daily their pups for nursing only once with circadian periodicity. Before the nursing events, they present increased activity and arousal, which shift according to the timing of scheduled nursing, either during the day or night. Brain areas related to maternal behavior and neuroendocrine cells for milk secretion are also entrained. The daily return of the doe for nursing at approximately the same hour suggests a motivational drive with circadian periodicity. Previously, we reported the activation of the mesolimbic system at the time of nursing, but not 12 h before that. Aiming at a better understanding of the mechanism of this anticipatory behavior, we explored the participation of the limbic regions of the amygdala and the bed nucleus of the stria terminalis, as well as the possible activation of the hypothalamic-pituitaryadrenal axis, specifically the corticotropin-releasing factor cells in the hypothalamic paraventricular nucleus of does at different times before and after nursing. The medial and cortical amygdala, the bed nucleus of the stria terminalis, and corticotropin cells showed activation only after nursing. However, the central amygdala was also activated before nursing. We conclude that the medial and the cortical amygdala form part of the afferent olfactory pathway for entrainment, and the central amygdala participates in the anticipatory motivational circuit of the control of periodic nursing. The lack of activation of corticotropin cells before nursing is consistent with the possible harmful effects of the doe's high glucocorticoid levels on the developing pups.

Sexual satiety modifies methamphetamine-induced locomotor and rewarding effects and dopamine-related protein levels in the striatum of male rats.

RATIONALE: Drug and natural rewarding stimuli activate the mesolimbic dopaminergic system. Both methamphetamine (Meth) and copulation to satiety importantly increase dopamine (DA) release in the nucleus accumbens (NAc), but with differences in magnitude. This paper analyzes the interaction between Meth administration and the intense sexual activity associated with sexual satiety. OBJECTIVES: To evaluate possible changes in Meth-induced behavioral effects and striatal DA-related protein expression due to sexual satiety. METHODS: Meth-induced locomotor activity and conditioned place preference (CPP) were tested in sexually experienced male rats that copulated to satiety (S-S) or ejaculated once (1E) the day before or displayed no sexual activity (control group; C). DA receptors and DA transporter expression were determined by western blot in the striatum of animals of all sexual conditions treated with specific Meth doses. RESULTS: Meth's locomotor and rewarding effects were exacerbated in S-S animals, while in 1E rats, only locomotor effects were enhanced. Sexual activity, by itself, modified DA-related protein expression in the NAc core and in the caudate-putamen (CPu), while Meth treatment alone changed their expression only in the NAc shell. Meth-induced changes in the NAc shell turned in the opposite direction when animals had sexual activity, and additional changes appeared in the NAc core and CPu of S-S rats. CONCLUSION: Sexual satiety sensitizes rats to Meth's behavioral effects and the Meth-induced striatal DA-related protein adaptations are modified by sexual activity, evidencing cross-sensitization between both stimuli.

Gut microbiota suppress feeding induced by palatable foods.

Feeding behaviors depend on intrinsic and extrinsic factors including genetics, food palatability, and the environment.1,2,3,4,5 The gut microbiota is a major environmental contributor to host physiology and impacts feeding behavior.6,7,8,9,10,11,12 Here, we explored the hypothesis that gut bacteria influence behavioral responses to palatable foods and reveal that antibiotic depletion (ABX) of the gut microbiota in mice results in overconsumption of several palatable foods with conserved effects on feeding dynamics. Gut microbiota restoration via fecal transplant into ABX mice is sufficient to rescue overconsumption of high-sucrose pellets. Operant conditioning tests found that ABX mice exhibit intensified motivation to pursue high-sucrose rewards. Accordingly, neuronal activity in mesolimbic brain regions, which have been linked with motivation and reward-seeking behavior,3 was elevated in ABX mice after consumption of high-sucrose pellets. Differential antibiotic treatment and functional microbiota transplants identified specific gut bacterial taxa from the family S24-7 and the genus Lactobacillus whose abundances associate with suppression of high-sucrose pellet consumption. Indeed, colonization of mice with S24-7 and Lactobacillus johnsonii was sufficient to reduce overconsumption of high-sucrose pellets in an antibiotic-induced model of binge eating. These results demonstrate that extrinsic influences from the gut microbiota can suppress the behavioral response toward palatable foods in mice.

Prenatal THC Exposure Induces Sex-Dependent Neuropsychiatric Endophenotypes in Offspring and Long-Term Disruptions in Fatty-Acid Signaling Pathways Directly in the Mesolimbic Circuitry.

Despite increased prevalence of maternal cannabis use, little is understood regarding potential long-term effects of prenatal cannabis exposure (PCE) on neurodevelopmental outcomes. While neurodevelopmental cannabis exposure increases the risk of developing affective/mood disorders in adulthood, the precise neuropathophysiological mechanisms in male and female offspring are largely unknown. Given the interconnectivity of the endocannabinoid (ECb) system and the brain's fatty acid pathways, we hypothesized that prenatal exposure to Δ9-tetrahydrocannabinol (THC) may dysregulate fetal neurodevelopment through alterations of fatty-acid dependent synaptic and neuronal function in the mesolimbic system. To investigate this, pregnant Wistar rats were exposed to vehicle or THC (3 mg/kg) from gestational day (GD)7 until GD22. Anxiety-like, depressive-like, and reward-seeking behavior, electrophysiology, and molecular assays were performed on adult male/female offspring. Imaging of fatty acids using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) was performed at prepubescence and adulthood. We report that PCE induces behavioral, neuronal, and molecular alterations in the mesolimbic system in male and female offspring, resembling neuropsychiatric endophenotypes. Additionally, PCE resulted in profound dysregulation of critical fatty acid pathways in the developing brain lipidome. Female progeny exhibited significant alterations to fatty acid levels at prepubescence but recovered from these deficits by early adulthood. In contrast, males exhibited persistent fatty acid deficits into adulthood. Moreover, both sexes maintained enduring abnormalities in glutamatergic/GABAergic function in the nucleus accumbens (NAc). These findings identify several novel long-term risks of maternal cannabis use and demonstrate for the first time, sex-related effects of maternal cannabinoid exposure directly in the developing neural lipidome.