Hyperdopaminergic states in mental disorders are associated with disruptive deficits in decision making. However, the precise contribution of topographically distinct mesencephalic dopamine pathways to decision-making processes remains elusive. Here we show, using a multidisciplinary approach, how hyperactivity of ascending projections from the ventral tegmental area (VTA) contributes to impaired flexible decision making in rats. Activation of the VTA–nucleus accumbens pathway leads to insensitivity to loss and punishment due to impaired processing of negative reward prediction errors. In contrast, activation of the VTA–prefrontal cortex pathway promotes risky decision making without affecting the ability to choose the economically most beneficial option. Together, these findings show how malfunction of ascending VTA projections affects value-based decision making, suggesting a potential mechanism through which increased forebrain dopamine signaling leads to aberrant behavior, as is seen in substance abuse, mania, and after dopamine replacement therapy in Parkinson’s disease.
Hyperdopaminergic states in mental disorders are associated with disruptive deficits in decision-making. However, the precise contribution of topographically distinct mesencephalic dopamine pathways to decision-making processes remains elusive. Here we show, using a multidisciplinary approach, how hyperactivity of ascending projections from the ventral tegmental area (VTA) contributes to faulty decision-making in rats. Activation of the VTA-nucleus accumbens pathway leads to insensitivity to loss and punishment due to impaired processing of negative reward prediction errors. In contrast, activation of the VTAprefrontal cortex pathway promotes risky decision-making without affecting the ability to choose the economically most beneficial option. Together, these findings show how malfunction of ascending VTA projections affects value-based decision-making, providing a mechanistic understanding of the reckless behaviors seen in substance abuse, mania, and after dopamine replacement therapy in Parkinson's disease.Impaired decision-making can have profound negative consequences, both in the short and in the long term. As such, it is observed in a variety of mental disorders, such as mania 1,2 , substance addiction [3][4][5][6] , and as a side effect of dopamine (DA) replacement therapy in Parkinson's disease 7,8 . Importantly, these disorders are associated with aberrations in DAergic neurotransmission 9,10 , and DA has been implicated in decision-making processes [11][12][13] . However, ascending DAergic projections from the ventral mesencephalon are anatomically and functionally heterogeneous [14][15][16] and the contribution of these distinct DA pathways to decision-making processes remains elusive.The mesocorticolimbic system, comprising DA cells within the ventral tegmental area (VTA) that mainly project to the nucleus accumbens (NAc; mesoaccumbens pathway) and medial prefrontal cortex (mPFC; mesocortical pathway), has an important role in value-based learning and decision-making [14][15][16] . When an experienced reward is better than expected, the firing of VTA DA neurons increases, thereby signaling a discrepancy between anticipated and experienced reward to downstream regions. Conversely, when a reward does not fulfill expectations, DA neuronal activity decreases. This pattern of DA cell activity is the basis of reward prediction error (RPE) theory [17][18][19][20] , which describes an essential mechanism through which organisms learn to flexibly alter their behavior when the costs and benefits associated with different courses of action shift. Although the relevance of RPEs in value-based learning is widely acknowledged, little is known about how different VTA target regions process these DA-mediated error signals, and how this ultimately leads to adaptations in behavior.Here, we used projection-specific chemogenetics combined with behavioral tasks, pharmacological interventions, computational modelling, in vivo microdialysis and in vivo neuronal population recordings to investigate how different ascending V...
Deep brain stimulation (DBS) of the nucleus accumbens (NAc) has proven to be an effective treatment for therapy refractory obsessive–compulsive disorder. Clinical observations show that anxiety symptoms decrease rapidly following DBS. As in clinical studies different regions are targeted, it is of principal interest to understand which brain area is responsible for the anxiolytic effect and whether high-frequency stimulation of different areas differentially affect unconditioned (innate) and conditioned (learned) anxiety. In this study, we examined the effect of stimulation in five brain areas in rats (NAc core and shell, bed nucleus of the stria terminalis (BNST), internal capsule (IC) and the ventral medial caudate nucleus (CAU)). The elevated plus maze was used to test the effect of stimulation on unconditioned anxiety, the Vogel conflict test for conditioned anxiety, and an activity test for general locomotor behaviour. We found different anxiolytic effects of stimulation in the five target areas. Stimulation of the CAU decreased both conditioned and unconditioned anxiety, while stimulation of the IC uniquely reduced conditioned anxiety. Remarkably, neither the accumbens nor the BNST stimulation affected conditioned or unconditioned anxiety. Locomotor activity increased with NAc core stimulation but decreased with the BNST. These findings suggest that (1) DBS may have a differential effect on unconditioned and conditioned anxiety depending on the stimulation area, and that (2) stimulation of the IC exclusively reduces conditioned anxiety. This suggests that the anxiolytic effects of DBS seen in OCD patients may not be induced by stimulation of the NAc, but rather by the IC.
Little is known about the effects of chronic fluoxetine on 5-HT transmission in the adolescent brain, even though it is acknowledged that the neuroplasticity of the brain during childhood and adolescence might influence the neurobiological mechanisms underlying treatment response. Also, possible ongoing effects on monoamine function following drug discontinuation are unidentified. We therefore examined the chronic effects of fluoxetine on extracellular 5-HT and dopamine concentrations in the medial prefrontal cortex and studied their responsiveness to an acute 5-HT challenge after a one-week washout period, both in adolescent and adult rats. Noradrenaline was measured in adult animals only. Fluoxetine increased 5-HT to 200–300% of control and DA and NA to 150% of control. Although there were no lasting effects of chronic fluoxetine on basal monoamine levels, we observed a clear potentiating effect of previous treatment on the fluoxetine-induced increase in extracellular 5-HT and, to a lesser extent, extracellular DA. No differential effect was found for noradrenaline. Age-at-treatment did not influence these results. So, after cessation of chronic fluoxetine treatment 5-HT responsiveness remains heightened. This may be indicative of the continuing presence of 5-HT receptor desensitization, at least until one week after drug discontinuation in rats. No apparent age-at-treatment effects on extracellular monoamine concentrations in the medial prefrontal cortex were detected, but age-related differences in 5-HT transmission further down-stream or in the recovery processes cannot be ruled out.
In animal models, devices such as indwelling catheters and intracranial cannulae are often fixed on the skull to allow sampling or injection in the freely moving animal. The most commonly used method to fixate these devices is by embedding them in a 'helmet' of cement which is fixed to the skull with screws. Methylmethacrylate cement is commonly used for this purpose. The disadvantages of this cement are the high polymerization temperature, poor bonding to the bone and long hardening time. We have evaluated the use of glass ionomer cement, carboxylat cement and cyanoacrylic glue as alternative for methylmethacrylate cement. Temperature increase during polymerization of methylmethacrylate cement and glass ionomer cement was measured in the cement on the skull and in the brain of 14 rats in an acute model. In a chronic model, 52 rats and 91 mice were equipped with a 'helmet' of one of the cements. The glass ionomer 'helmets' were applied without or with pretreatment of the skull. The attachment of the cement to the skull was checked every day. After four weeks the bonding strengths of the cements were measured. The glass ionomer cement had less temperature increase during polymerization and good bonding capabilities when compared with methylmethacrylate cement. Mechanical pretreatment of the skull resulted in a significant increase in bonding strength of glass ionomer cement in mice and rats as compared with chemical pretreatment. Furthermore, glass ionomer cement had a shorter hardening time than methylmethacrylate cement, and when the glass ionomer cement was used in prepacked capsules, it was possible to apply the cement sterilely and easily. Cyanoacrylic glue had good bonding capabilities to the skull of mice and is also a good substitute for methylmethacrylate cement.
To study the effectiveness of high-dose atropine for reducing eye growth in Mendelian myopia in children and mice. Methods: We studied the effect of high-dose atropine in children with progressive myopia with and without a monogenetic cause. Children were matched for age and axial length (AL) in their first year of treatment. We considered annual AL progression rate as the outcome and compared rates with percentile charts of an untreated general population. We treated C57BL/6J mice featuring the myopic phenotype of Donnai-Barrow syndrome by selective inactivation of Lrp2 knock out (KO) and control mice (CTRL) daily with 1% atropine in the left eye and saline in the right eye, from postnatal days 30-56. Ocular biometry was measured using spectral-domain optical coherence tomography. Retinal dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were measured using high-performance liquid chromatography. Results: Children with a Mendelian form of myopia had average baseline spherical equivalent (SE) -7.6 ± 2.5D and AL 25.8 ± 0.3 mm; children with non-Mendelian myopia had average SE −7.3 ± 2.9 D and AL 25.6 ± 0.9 mm. During atropine treatment, the annual AL progression rate was 0.37 ± 0.08 and 0.39 ± 0.05 mm in the Mendelian myopes and non-Mendelian myopes, respectively. Compared with progression rates of untreated general population (0.47 mm/year), atropine reduced AL progression with 27% in Mendelian myopes and 23% in non-Mendelian myopes. Atropine significantly reduced AL growth in both KO and CTRL mice (male, KO: −40 ± 15; CTRL: −42 ± 10; female, KO: −53 ± 15; CTRL: −62 ± 3 μm). The DA and DOPAC levels 2 and 24 h after atropine treatment were slightly, albeit non-significantly, elevated. Conclusions: High-dose atropine had the same effect on AL in high myopic children with and without a known monogenetic cause. In mice featuring a severe form of Mendelian myopia, atropine reduced AL progression. This suggests that atropine can reduce myopia progression even in the presence of a strong monogenic driver.
Highlights We combined deep brain stimulation with amperometric measurements of oxygen in the mouse brain. The effects of behavioural stimuli like novelty were easily detectable. DBS was shown to reduce the effects of novelty in the striatum. The method allows chronic studies of DBS effects on brain activity in freely-moving mice.
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