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Baseline levels of impulsive choice. Both high impulsive (HI) and low impulsive (LI) groups of rats are evident in the cue and no cue conditions. Data shown represent the average of five stable postoperative sessions ± SEM
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Individual differences in impulsive decision-making may be critical determinants of vulnerability to impulse control disorders and substance abuse, yet little is known of their biological or behavioural basis. The orbitofrontal cortex (OFC) has been heavily implicated in the regulation of impulsive decision-making. However, lesions of the OFC in ra...
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... et al. 2003b). Those who chose the large reward lever more than 75% of the time when lever choice was averaged at the 0 s and 15 s delays were labelled as low impulsive (LI), and the remainder of the animals were labelled as high impulsive (HI), resulting in the identification of seven LI and nine HI animals in both the No Cue and Cue groups (Fig. 3). This classification of impulsivity level produced a significant between-subjects effect in the analysis of baseline behav- iour in both the No Cue (impulsivity level: F 1, 14 =10.129, p<0.007) and Cue groups (impulsivity level: F 1, 14 = 44.513, p<0.0001), suggesting that the choice behaviour of these two groups can be meaningfully ...
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... Furthermore, Pcdh15 deletion correlated with increased impulsivity (Fig. 2c). The orbitofrontal cortex is implicated in impulsivity [80] and structurally altered in patients with BD [81]. It interacts with the amygdala, thereby suppressing its activity [82]. ...
Genetic factors significantly affect the pathogenesis of psychiatric disorders. However, the specific pathogenic mechanisms underlying these effects are not fully understood. Recent extensive genomic studies have implicated the protocadherin-related 15 (PCDH15) gene in the onset of psychiatric disorders, such as bipolar disorder (BD). To further investigate the pathogenesis of these psychiatric disorders, we developed a mouse model lacking Pcdh15. Notably, although PCDH15 is primarily identified as the causative gene of Usher syndrome, which presents with visual and auditory impairments, our mice with Pcdh15 homozygous deletion (Pcdh15-null) did not exhibit observable structural abnormalities in either the retina or the inner ear. The Pcdh15-null mice showed very high levels of spontaneous motor activity which was too disturbed to perform standard behavioral testing. However, the Pcdh15 heterozygous deletion mice (Pcdh15-het) exhibited enhanced spontaneous locomotor activity, reduced prepulse inhibition, and diminished cliff avoidance behavior. These observations agreed with the symptoms observed in patients with various psychiatric disorders and several mouse models of psychiatric diseases. Specifically, the hyperactivity may mirror the manic episodes in BD. To obtain a more physiological, long-term quantification of the hyperactive phenotype, we implanted nano tag® sensor chips in the animals, to enable the continuous monitoring of both activity and body temperature. During the light-off period, Pcdh15-null exhibited elevated activity and body temperature compared with wild-type (WT) mice. However, we observed a decreased body temperature during the light-on period. Comprehensive brain activity was visualized using c-Fos mapping, which was assessed during the activity and temperature peak and trough. There was a stark contrast between the distribution of c-Fos expression in Pcdh15-null and WT brains during both the light-on and light-off periods. These results provide valuable insights into the neural basis of the behavioral and thermal characteristics of Pcdh15-deletion mice. Therefore, Pcdh15-deletion mice can be a novel model for BD with mania and other psychiatric disorders, with a strong genetic component that satisfies both construct and surface validity.
... Animal studies support these findings and show that lesions in the prefrontal cortex and ventral striatum (i.e. nucleus accumbens) alter delay discounting behavior 28,29 . In particular, the medial prefrontal cortex (mPFC) seems to play a key role in this behavior. ...
... The fact that the effects of ISD on delay discounting behavior depend on inherent impulsivity is remarkable and requires further discussion. Previous studies have shown that the inactivation of the orbitofrontal cortex 29 and the nucleus accumbens 4 produces different effects on delay discounting depending on the basal levels of impulsivity, and suggested that low and high impulsivity have different neurobiological substrates 55 . In support of this idea, evidence shows that a higher number of D2 dopamine receptors in the mPFC 46 and the nucleus Table 2. LR and SR choices for control and stress high impulsive animals (HI) at each delay for LR (1 s, 10 s and 20 s) and across sessions during the delay discounting task (see Fig. 3). ...
... Based on these studies and our current work, we hypothesize that females will show higher choice impulsivity and PNNs densities in the mPFC compared to males after ISD. Second, previous work has shown that increases in delay discounting behavior depend on the order in which delays are presented and/or reward-related cues 29,54,66,67 . Regarding delay presentation, some studies have shown that the administration of amphetamine increases or decreases discounting behavior depending on the order of delay presentation 54,66 , and suggest that the effects of amphetamine reflect perseveration and not intertemporal decision-making deficits. ...
Repeated stress can predispose to substance abuse. However, behavioral and neurobiological adaptations that link stress to substance abuse remain unclear. This study investigates whether intermittent social defeat (ISD), a stress protocol that promotes drug-seeking behavior, alters intertemporal decision-making and cortical inhibitory function in the medial prefrontal cortex (mPFC). Male long evans rats were trained in a delay discounting task (DDT) where rats make a choice between a fast (1 s) small reward (1 sugar pellet) and a large reward (3 sugar pellets) that comes with a time delay (10 s or 20 s). A decreased preference for delayed rewards was used as an index of choice impulsivity. Rats were exposed to ISD and tested in the DDT 24 h after each stress episode, and one- and two-weeks after the last stress episode. Immunohistochemistry was performed in rat’s brains to evaluate perineuronal nets (PNNs) and parvalbumin GABA interneurons (PV) labeling as markers of inhibitory function in mPFC. ISD significantly decreased the preference for delayed large rewards in low impulsive, but not high impulsive, animals. ISD also increased the density of PNNs in the mPFC. These results suggest that increased choice impulsivity and cortical inhibition predispose animals to seek out rewards after stress.
... Imaging studies find that changes in the function of fronto-striatal pathways are correlated to individual differences in choice impulsivity 25,26 . Animal studies support these findings and show that lesions in the prefrontal cortex and ventral striatum (i.e., nucleus accumbens) alter delay discounting behavior 27,28 . In particular, the medial prefrontal cortex (mPFC) seems to play a key role in this behavior. ...
... This study has limitations. Previous work has shown that increases in delay discounting behavior depend on the order in which delays are presented and/or reward-related cues 28,51,61 . Regarding delay presentation, some studies have shown that the administration of amphetamine increases or decreases discounting behavior depending on the order of delay presentation 51,61 , and suggest that the effects of amphetamine reflect perseveration and not intertemporal decision-making deficits. ...
Repeated stress can predispose to substance abuse. However, behavioral and neurobiological adaptations that link stress to substance abuse remain unclear. This study investigates whether Intermittent Social Defeat (ISD), a stress protocol that promotes drug-seeking behavior, alters intertemporal decision-making and cortical inhibitory function in the medial prefrontal cortex (mPFC). Male Long Evans rats were trained in a delay discounting task (DDT) where rats make a choice between a fast (1s) small reward (1 sugar pellet) and a large (3 sugar pellets) reward that comes with a time delay (10 or 20s). A decreased preference for delayed rewards was used as an index of choice impulsivity. Rats were exposed to ISD and tested in DDT 24 hours after each stress episode, and one-and two-weeks after the last stress episode. Immunohistochemistry was performed in rats brains to evaluate perineuronal nets (PNNs) and parvalbumin GABA interneurons (PV) labeling as markers of inhibitory function in the mPFC. In the DDT, ISD significantly decreased the preference for delayed large rewards, in the short and long term. ISD also increased the density of PNNs in the mPFC. These results suggest that increased choice impulsivity and cortical inhibition predispose animals to seek out rewards after stress.
... Some report increased sensitivity to delay costs with D2R antagonism [20,54], whereas others show no effect with either antagonists or agonists [2,55,56]. Such discrepancies may relate, to some extent, to the combined impact of these agents on NAc and relevant extrastriatal regions (e.g., prefrontal cortex, amygdala, and ventral tegmental area), whose D2R signaling may have varied roles in impulsive decision-making [57][58][59][60][61] . However, the few studies that have performed intra-NAc microinfusions of raclopride, eticlopride or quinpirole have shown no effect of NAc D2R in delay discounting [62,63]. ...
Impulsive choice, often characterized by excessive preference for small, short-term rewards over larger, long-term rewards, is a prominent feature of substance use and other neuropsychiatric disorders. The neural mechanisms underlying impulsive choice are not well understood, but growing evidence implicates nucleus accumbens (NAc) dopamine and its actions on dopamine D2 receptors (D2Rs). Because several NAc cell types and afferents express D2Rs, it has been difficult to determine the specific neural mechanisms linking NAc D2Rs to impulsive choice. Of these cell types, cholinergic interneurons (CINs) of the NAc, which express D2Rs, have emerged as key regulators of striatal output and local dopamine release. Despite these relevant functions, whether D2Rs expressed specifically in these neurons contribute to impulsive choice behavior is unknown. Here, we show that D2R upregulation in CINs of the mouse NAc increases impulsive choice as measured in a delay discounting task without affecting reward magnitude sensitivity or interval timing. Conversely, mice lacking D2Rs in CINs showed decreased delay discounting. Furthermore, CIN D2R manipulations did not affect probabilistic discounting, which measures a different form of impulsive choice. Together, these findings suggest that CIN D2Rs regulate impulsive decision-making involving delay costs, providing new insight into the mechanisms by which NAc dopamine influences impulsive behavior.
... De plus, une stimulation du COF chez des souris entraînées à appuyer sur des leviers augmente les actions à but dirigées et limite celles guidées par un comportement d'habitude (Gremel et al., 2016). Une lésion spécifique de cette région provoque chez l'animal une préférence pour les choix inadaptés et risqués (Pais-Vieira et al., 2007;Zeeb et al., 2010). ...
L’addiction aux drogues est considérée comme un trouble psychiatrique chronique caractérisé par une recherche et une prise compulsive de drogue et par un fort taux de récidive. Mes travaux de thèse s’organisent en 2 axes. Dans le premier axe, nous avons développé une nouvelle procédure comportementale pour étudier le comportement compulsif vis-à-vis de la nourriture qui prenne en considération le niveau de résistance individuel (article1). Pour la suite, avec cette procédure, nous avons réalisé une investigation comportementale sur l’influence d’un régime riche en graisse et en sucre sur le développement d’une addiction à la nourriture. En effet, l’une des questions encore non résolues est de savoir si les effets observés suite à une exposition à un régime palatable persistent ou disparaissent après un certain temps. De plus, nous avons cherché à savoir si le sexe de l’animal ou l’âge d’exposition pouvait être des facteurs de vulnérabilité. Les résultats obtenus montrent que l’exposition chronique à de nourriture riche en sucre et en graisse n’a pas d’effet persistant sur la motivation et la résistance à la punition des animaux et que ni le sexe ni l’âge n’avaient d’influence majeure sur la compulsivité à consommer une récompense sucrée (article 2).Dans le second axe, nous avons étudié si le métabolisme du cholestérol cérébral pouvait représenter une nouvelle cible thérapeutique pour prévenir la rechute et traiter l’addiction. Dans ce but, nous avons modulé le métabolisme cérébral du cholestérol grâce à des vecteur viraux au sein de structures impliquées dans l'addiction et étudier les effets bénéfiques potentiels sur les comportements d’addiction (article 3). Ainsi, après des sessions d’auto-administration de cocaïne, nous avons surexprimé la cholestérol hydroxylase (gène CYP46A1), l’enzyme de dégradation du cholestérol principalement trouvée dans le cerveau et étudié les effets de cette modulation sur la rechute. Les résultats ont montré que la surexpression de CYP46A1 dans le striatum dorsal (Dst), pendant la période d’abstinence, a réduit la recherche de drogue chez des rats addicts. La surexpression de CYP46A1 dans le cortex cingulaire antérieur et le noyau accumbens n’a pas eu d’effet. Des investigations supplémentaires ont montré que la surexpression de CYP46A1 dans le DSt ne modifie pas le comportement de recherche d’une récompense naturelle ou dans d’autres comportements pendant la phase de consommation de la drogue, à savoir la résistance à la punition et la motivation. Pour cela, le virus a été injecté avant la première exposition à la drogue. Ces observations indiquent que le métabolisme du cholestérol joue un rôle dans l’addiction et que la manipulation de cette voie métabolique pendant une période d’abstinence, spécifiquement dans le DSt, pourrait avoir des effets bénéfiques pour prévenir la rechute. Ces résultats montrent que le métabolisme du cholestérol, spécifiquement dans le DSt, représente une potentielle nouvelle cible thérapeutique pour prévenir la rechute et traiter l’addiction.
... Neurons in the basolateral amygdala (BLA) receive input and output from posterior piriform cortex (PPC) or orbitofrontal cortex (OFC) in the circuitry that drives responses to changed odor cues in a reversal learning task [6][7][8]. Circuits containing axonal projections from the BLA to the nucleus accumbens (NAc), OFC or medial prefrontal cortex (mPFC) neurons play unique roles in altering behavioral responses when a cue is devalued [9][10][11][12][13]. These data suggest that the BLA might be a critical brain area for integrating previous information with new changes in odor cues or delay time to appropriately alter behavior. ...
... LFP powers (theta, 4-12 Hz) were statistically analyzed in the stage of pre-learning during reversal process in 5-month-SAMR1 mice and 5-month-SAMP8 mice (O). The change of LFP powers (4)(5)(6)(7)(8)(9)(10)(11)(12) in the stage of learning and learnt were measured relative to 30 sec baseline segments (pre-learning phase) in SAMR1 mice and SAMP8 mice (P). The learning time was analyzed in the phase of learning during reversal between SAMR1 mice and SAMP8 mice (Q). ...
Aging is characterized with a progressive decline in many cognitive functions, including behavioral flexibility, an important ability to respond appropriately to changing environmental contingencies. However, the underlying mechanisms of impaired behavioral flexibility in aging are not clear. In this study, we reported that necroptosis-induced reduction of neuronal activity in the basolateral amygdala (BLA) plays an important role in behavioral inflexibility in 5-month-old mice of the senescence-accelerated mice prone-8 (SAMP8) line, a well-established model with age-related phenotypes. Application of Nec-1s, a specific inhibitor of necroptosis, reversed the impairment of behavioral flexibility in SAMP8 mice. We further observed that the loss of glycogen synthase kinase 3α (GSK-3α) was strongly correlated with necroptosis in the BLA of aged mice and the amygdala of aged cynomolgus monkeys (Macaca fascicularis). Moreover, genetic deletion or knockdown of GSK-3α led to the activation of necroptosis and impaired behavioral flexibility in wild-type mice, while the restoration of GSK-3α expression in the BLA arrested necroptosis and behavioral inflexibility in aged mice. We further observed that GSK-3α loss resulted in the activation of mTORC1 signaling to promote RIPK3-dependent necroptosis. Importantly, we discovered that social isolation, a prevalent phenomenon in aged people, facilitated necroptosis and behavioral inflexibility in 4-month-old SAMP8 mice. Overall, our study not only revealed the molecular mechanisms of the dysfunction of behavioral flexibility in aged people but also identified a critical lifestyle risk factor and a possible intervention strategy.
... Neuroimaging and lesion evidence converge to indicate that the medial orbitofrontal cortex (mOFC)-a region crucially involved in the attribution of "common currency" subjective value to rewards and in impulsive conduct [32][33][34]-is necessary for delayed gratification [35][36][37][38][39]. In line with this, patients with a lesion to the mOFC-as compared to control patients and healthy participants-tend to show an increased preference for smaller immediate rewards over larger delayed ones, regardless of the kind of reward at stake [8,[40][41][42]. ...
Despite the widespread use of the delay discounting task in clinical and non-clinical contexts, several task versions are available in the literature, making it hard to compare results across studies. Moreover, normative data are not available to evaluate individual performances. The present study aims to propose a unified version of the delay discounting task based on monetary rewards and it provides normative values built on an Italian sample of 357 healthy participants. The most used parameters in the literature to assess the delay discount rate were compared to find the most valid index to discriminate between normative data and a clinical population who typically present impulsivity issues, i.e., patients with a lesion to the medial orbitofrontal cortex (mOFC). In line with our hypothesis, mOFC patients showed higher delay discounting scores than the normative sample and the normative group. Based on this evidence, we propose that the task and indexes here provided can be used to identify extremely high (above the 90th percentile for hyperbolic k or below the 10th percentile for AUC) or low (below the 10th percentile for hyperbolic k or above the 90th percentile for AUC) delay discounting performances. The complete dataset, the R code used to perform all analyses, a free and modifiable version of the delay discounting task, as well as the R code that can be used to extract all indexes from such tasks and compare subjective performances with the normative data here presented are available as online materials.
... Cues present in the environment can also influence the adoption of a behavioural 433 strategy; the considerable literature on sign-trackers vs goal-trackers may best exemplify the 434 significant individual differences in how such cues can be used to guide behaviour (Flagel et al., 435 2009; Saunders and Robinson, 2010; Flagel et al., 2011; Saunders and Robinson, 2013).436Illuminating a cue light during lengthy delays between response and reward delivery can 437 decrease delay discounting (i.e., reduction in a reward's subjective value due to waiting period)438 in rats(Cardinal et al., 2000). However, the presence of this cue does not eliminate the large 439 individual differences in animals' preferences for smaller-sooner vs larger-later rewards.440Inactivation of the lOFC only reduced choice of the larger-later reward in rats that showed a high 441 baseline preference for this option; an effect that was also observed following local infusions of 442 dopamine antagonists(Zeeb et al., 2010). Thus, the hypothesis that recruitment of the lOFC into 443 the decision-making process depends on the presence of cues, and that decision-making patterns444 21 ...
Previous research has indicated that reward-paired cues can enhance disadvantageous risky choice in both humans and rodents. Systemic administration of a serotonin 2C receptor antagonist can attenuate this cue-induced risk preference in rats. However, the neurocognitive mechanisms mediating this effect are currently unknown. We therefore assessed whether the serotonin 2C receptor antagonist RS 102221 is able to attenuate cue-enhanced risk preference via its actions in the lateral orbitofrontal cortex (lOFC) or prelimbic (PrL) area of the medial prefrontal cortex (mPFC). A total of 32 male Long-Evans rats were trained on the cued version of the rat gambling task (rGT), a rodent analog of the human Iowa gambling task, and bilateral guide cannulae were implanted into the lOFC or PrL. Intra-lOFC infusions of the 5-HT2C antagonist RS 102221 reduced risky choice in animals that showed a preference for the risky options of the rGT at baseline. This effect was not observed in optimal decision-makers, nor those that received infusions targeting the PrL. Given prior data showing that 5-HT2C antagonists also improve reversal learning through the same neural locus, we hypothesized that reward-concurrent cues may amplify risky decision-making through cognitive inflexibility. We therefore devalued the sugar pellet rewards used in the cued rGT (crGT) through satiation and observed that decision-making patterns did not shift unless animals also received intra-lOFC RS 102221. Collectively, these data suggest that the lOFC is one critical site through which reward-concurrent cues promote risky choice patterns that are insensitive to reinforcer devaluation, and that 5-HT2C antagonism may optimize choice by facilitating exploration.
... In light of the previously determined connectivity between the prefrontal cortex (PFC) and the midbrain ( To glean more insights in the latter observations, we assessed the projections within the more ventral PFC subdivision of the orbitofrontal cortex (OFC). Although the influence of DA within this frontal part of the brain has been less established than in its more dorsal counterparts (DPFC/VLPFC (Williams and Goldman-Rakic, 1998)), deficits in DA to this structure affect various cognitive functions in several animal models (Walker et al., 2009, Zeeb et al., 2010. In all monkeys, overall innervations were stronger in the OFC compared to the subdivisions in the PFC discussed above. ...
Animals adapt their behavior to adjust to dynamically changing environments. One of the important neurotransmitter systems that are implicated in shaping this behavior is dopamine (DA). In the current manuscript, we investigate this neurotransmitter system, which is involved in a wide range of functions, including but not limited to: motor control, decision-making, attention, memory and sensory processing. During the last few decades, neurophysiologists and anatomists have explored the DA neurotransmitter network. Undoubtedly, these studies have provided key knowledge on the DA network and its functions, but still, voids remain in complete understanding. We aimed to reveal the DA connectome by using recently developed viral vector mediated tracers. The first purpose of this dissertation is to gain better insights into the brain-wide structural connections originating in the ventral midbrain DA system using anterograde viral vector-based methods.
In chapter 2, we investigated the detailed anatomical connectivity of the midbrain DA system. Therefore, we injected adeno associated viral vector (AAV) mediated tracers into the macaque’s midbrain, using magnetic resonance imaging (MRI) guidance. Subsequently, we carefully mapped the brain-wide anatomical connections originating from the (injected) midbrain region. This in-depth study revealed dopaminergic projections at both areal- and laminar-level. We found that the lateral ventral midbrain (including substantia nigra, pars compacta (SNc)) projects densely to somatomotor cortex and dorsal striatum. In contrast, the medial midbrain (primarily the ventral tegmental area (VTA)) projects to dorsal prefrontal and temporal cortical areas, with surprisingly sparse projections to the striatum. In general, the orbitofrontal and occipito-parietal cortex received strong and weak projections, respectively. Overall, the ventral midbrain is found to project to many brain regions, although in a very heterogeneous manner.
Our second study is completely independent from the first one and explores training-based changes in neuronal processing in early visual cortical areas, which are most likely partially driven by dopaminergic signals. Hence this study aims not to investigate the anatomical features of the dopaminergic system, but rather a functional consequence of its activation under normal circumstances. Visual processing involves both retinal feedforward and non-retinal feedback signal inputs. It is largely unknown, however, how non-saccadic somatomotor signals influence early visual processing in NHPs. In chapter 3, we designed an event-related functional magnetic resonance imaging (fMRI) paradigm to investigate the modulations in the neuronal activity in early visual areas after associating an effector with a visual stimulus. We found lateralized activity modulations in the visual cortical areas ipsilateral to somatomotor areas activated by the associated effector. The (enhanced) activity in ipsilateral early visual areas most likely reflect the influence of somatomotor signals induced by the effector which is associated with the visual stimulus.
In conclusion, the first study findings reported in this dissertation enhanced our understanding of the midbrain DA structural network and the second study revealed the influence of somatomotor signals in early visual processing.
... Delayed rewards typically have less subjective value than immediately-available rewards, a phenomenon known as delay discounting (DD) [15]. To determine whether adult neurogenesis promotes the choice of future rewards, we used the transgenic GFAP-TK rat model to deplete neurogenesis [7] and a DD decision-making task that has been optimized for rats [43] (timeline in Fig. 1A). As measured by the immature neuronal marker, DCX, neurogenesis was reduced in valganciclovir-treated TK rats by 94% in the dorsal DG and 77% in the ventral DG, compared to valganciclovir-treated wild type (WT) littermates (Fig. 1B, C; hereafter, "WT" and "TK" refers to valganciclovirtreated animals, and "WT veh" and "TK veh" refers to vehicle-treated animals in control experiments). ...
Adult hippocampal neurogenesis has been implicated in a number of disorders where reward processing is disrupted but whether new neurons regulate specific aspects of reward-related decision making remains unclear. Given the role of the hippocampus in future-oriented cognition, here we tested whether adult neurogenesis regulates preference for future, advantageous rewards in a delay discounting paradigm for rats. Indeed, blocking neurogenesis caused a profound aversion for delayed rewards, and biased choice behavior toward immediately available, but smaller, rewards. Consistent with a role for the ventral hippocampus in impulsive decision making and future-thinking, neurogenesis-deficient animals displayed reduced activity in the ventral hippocampus. In intact animals, delay-based decision making restructured dendrites and spines in adult-born neurons and specifically activated adult-born neurons in the ventral dentate gyrus, relative to dorsal activation in rats that chose between immediately-available rewards. Putative developmentally-born cells, located in the superficial granule cell layer, did not display task-specific activity. These findings identify a novel and specific role for neurogenesis in decisions about future rewards, thereby implicating newborn neurons in disorders where short-sighted gains are preferred at the expense of long-term health.
