Involvement of A13 dopaminergic neurons in prehensile movements but not reward in the rat.

Tyrosine hydroxylase (TH)-containing neurons of the dopamine (DA) cell group A13 are well positioned to impact known DA-related functions as their descending projections innervate target regions that regulate vigilance, sensory integration, and motor execution. Despite this connectivity, little is known regarding the functionality of A13-DA circuits. Using TH-specific loss-of-function methodology and techniques to monitor population activity in transgenic rats in vivo, we investigated the contribution of A13-DA neurons in reward and movement-related actions. Our work demonstrates a role for A13-DA neurons in grasping and handling of objects but not reward. A13-DA neurons responded strongly when animals grab and manipulate food items, whereas their inactivation or degeneration prevented animals from successfully doing so-a deficit partially attributed to a reduction in grip strength. By contrast, there was no relation between A13-DA activity and food-seeking behavior when animals were tested on a reward-based task that did not include a reaching/grasping response. Motivation for food was unaffected, as goal-directed behavior for food items was in general intact following A13 neuronal inactivation/degeneration. An anatomical investigation confirmed that A13-DA neurons project to the superior colliculus (SC) and also demonstrated a novel A13-DA projection to the reticular formation (RF). These results establish a functional role for A13-DA neurons in prehensile actions that are uncoupled from the motivational factors that contribute to the initiation of forelimb movements and help position A13-DA circuits into the functional framework regarding centrally located DA populations and their ability to coordinate movement

Hyperconnectivity of the ventromedial prefrontal cortex in obsessive-compulsive disorder.

Neuroimaging research has highlighted maladaptive thalamo-cortico-striatal interactions in obsessive-compulsive disorder as well as a more general deficit in prefrontal functioning linked with compromised executive functioning. More specifically, dysfunction in the ventromedial prefrontal cortex, a central hub in coordinating flexible behaviour, is thought to be central to obsessive-compulsive disorder symptomatology. We sought to determine the intrinsic alterations of the ventromedial prefrontal cortex in obsessive-compulsive disorder employing resting-state functional connectivity magnetic resonance imaging analyses with a ventromedial prefrontal cortex seed region of interest. A total of 38 obsessive-compulsive disorder patients and 33 matched controls were included in our analyses. We found widespread ventromedial prefrontal cortex hyperconnectivity during rest in patients with obsessive-compulsive disorder, displaying increased connectivity with its own surrounding region in addition to hyperconnectivity with several areas along the thalamo-cortico-striatal loop: thalamus, caudate and frontal gyrus. Obsessive-compulsive disorder patients also exhibited increased functional connectivity from the ventromedial prefrontal cortex to temporal and occipital lobes, cerebellum and the motor cortex, reflecting ventromedial prefrontal cortex hyperconnectivity in large-scale brain networks. Furthermore, hyperconnectivity of the ventromedial prefrontal cortex and caudate correlated with obsessive-compulsive disorder symptomatology. Additionally, we used three key thalamo-cortico-striatal regions that were hyperconnected with our ventromedial prefrontal cortex seed as supplementary seed regions, revealing hypoconnectivity along the orbito- and lateral prefrontal cortex-striatal pathway. Taken together, these results confirm a central role of a hyperconnected ventromedial prefrontal cortex in obsessive-compulsive disorder, with a special role for maladaptive crosstalk with the caudate, and indications for hypoconnectivity along the lateral and orbito pathways

Nicotinic α4 Receptor-Mediated Cholinergic Influences on Food Intake and Activity Patterns in Hypothalamic Circuits.

Nicotinic acetylcholine receptors (nAChRs) play an important role in regulating appetite and have been shown to do so by influencing neural activity in the hypothalamus. To shed light on the hypothalamic circuits governing acetylcholine's (ACh) regulation of appetite this study investigated the influence of hypothalamic nAChRs expressing the α4 subunit. We found that antagonizing the α4β2 nAChR locally in the lateral hypothalamus with di-hydro-ß-erythroidine (DHβE), an α4 nAChR antagonist with moderate affinity, caused an increase in food intake following free access to food after a 12 hour fast, compared to saline-infused animals. Immunocytochemical analysis revealed that orexin/hypocretin (HO), oxytocin, and tyrosine hydroxylase (TH)-containing neurons in the A13 and A12 of the hypothalamus expressed the nAChR α4 subunit in varying amounts (34%, 42%, 50%, and 51%, respectively) whereas melanin concentrating hormone (MCH) neurons did not, suggesting that DHβE-mediated increases in food intake may be due to a direct activation of specific hypothalamic circuits. Systemic DHβE (2 mg/kg) administration similarly increased food intake following a 12 hour fast. In these animals a subpopulation of orexin/hypocretin neurons showed elevated activity compared to control animals and MCH neuronal activity was overall lower as measured by expression of the immediate early gene marker for neuronal activity cFos. However, oxytocin neurons in the paraventricular hypothalamus and TH-containing neurons in the A13 and A12 did not show differential activity patterns. These results indicate that various neurochemically distinct hypothalamic populations are under the influence of α4β2 nAChRs and that cholinergic inputs to the lateral hypothalamus can affect satiety signals through activation of local α4β2 nAChR-mediated transmission.This work was supported by the Royal Society and the European Union (Latin America/European Liason, LAEL).This is the final version of the article. It first appeared from PLOS via http://dx.doi.org/1371/journal.pone.013332

Accumbal Cholinergic Interneurons Differentially Influence Motivation Related to Satiety Signaling

Satiety, rather than all or none, can instead be viewed as a cumulative decrease in the drive to eat that develops over the course of a meal. The nucleus accumbens (NAc) is known to play a critical role in this type of value reappraisal, but the underlying circuits that influence such processes are unclear. Although NAc cholinergic interneurons (CINs) comprise only a small proportion of NAc neurons, their local impact on reward-based processes provides a candidate cell population for investigating the neural underpinnings of satiety. The present research therefore aimed to determine the role of NAc-CINs in motivation for food reinforcers in relation to satiety signaling. Through bidirectional control of CIN activity in mice, we show that when motivated by food restriction, increasing CIN activity led to a reduction in palatable food consumption while reducing CIN excitability enhanced food intake. These activity-dependent changes developed only late in the session and were unlikely to be driven by the innate reinforcer strength, suggesting that CIN modulation was instead impacting the cumulative change in motivation underlying satiety signaling. We propose that on a circuit level, an overall increase in inhibitory tone onto NAc output neurons played a role in the behavioral results, as activating NAc-CINs led to an inhibition of medium spiny neurons that was dependent on nicotinic receptor activation. Our results reveal an important role for NAc-CINs in controlling motivation for food intake and additionally provide a circuit-level framework for investigating the endogenous cholinergic circuits that signal satiety.Peer reviewe

Impaired cognitive plasticity and goal-directed control in adolescent obsessive-compulsive disorder.

BACKGROUND: Youths with obsessive-compulsive disorder (OCD) experience severe distress and impaired functioning at school and at home. Critical cognitive domains for daily functioning and academic success are learning, memory, cognitive flexibility and goal-directed behavioural control. Performance in these important domains among teenagers with OCD was therefore investigated in this study. METHODS: A total of 36 youths with OCD and 36 healthy comparison subjects completed two memory tasks: Pattern Recognition Memory (PRM) and Paired Associates Learning (PAL); as well as the Intra-Extra Dimensional Set Shift (IED) task to quantitatively gauge learning as well as cognitive flexibility. A subset of 30 participants of each group also completed a Differential-Outcome Effect (DOE) task followed by a Slips-of-Action Task, designed to assess the balance of goal-directed and habitual behavioural control. RESULTS: Adolescent OCD patients showed a significant learning and memory impairment. Compared with healthy comparison subjects, they made more errors on PRM and PAL and in the first stages of IED involving discrimination and reversal learning. Patients were also slower to learn about contingencies in the DOE task and were less sensitive to outcome devaluation, suggesting an impairment in goal-directed control. CONCLUSIONS: This study advances the characterization of juvenile OCD. Patients demonstrated impairments in all learning and memory tasks. We also provide the first experimental evidence of impaired goal-directed control and lack of cognitive plasticity early in the development of OCD. The extent to which the impairments in these cognitive domains impact academic performance and symptom development warrants further investigation.This work was funded by a Wellcome Trust Grant (grant number 089589/Z/09/Z) awarded to TW Robbins, BJ Everitt, AC Roberts, JW Dalley, and BJ Sahakian, and a Wellcome Trust Senior Investigator Award (104631/Z/14/Z) to TW Robbins. The research was conducted in the Behavioural and Clinical Neuroscience Institute, which is supported by a joint award from the Medical Research Council and Wellcome Trust (G00001354). J Gottwald was supported by a BCNI MRC PhD studentship and St John’s College, Cambridge

Perseveration and Shifting in Obsessive-Compulsive Disorder as a Function of Uncertainty, Punishment, and Serotonergic Medication

© 2023 The Author(s). Published by Elsevier Inc on behalf of the Society of Biological Psychiatry. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/Background The nature of cognitive flexibility deficits in obsessive-compulsive disorder (OCD), which historically have been tested with probabilistic reversal learning tasks, remains elusive. Here, a novel deterministic reversal task and inclusion of unmedicated patients in the study sample illuminated the role of fixed versus uncertain rules/contingencies and of serotonergic medication. Additionally, our understanding of probabilistic reversal was enhanced through theoretical computational modeling of cognitive flexibility in OCD. Methods We recruited 49 patients with OCD, 21 of whom were unmedicated, and 43 healthy control participants matched for age, IQ, and gender. Participants were tested on 2 tasks: a novel visuomotor deterministic reversal learning task with 3 reversals (feedback rewarding/punishing/neutral) measuring accuracy/perseveration and a 2-choice visual probabilistic reversal learning task with uncertain feedback and a single reversal measuring win-stay and lose-shift. Bayesian computational modeling provided measures of learning rate, reinforcement sensitivity, and stimulus stickiness. Results Unmedicated patients with OCD were impaired on the deterministic reversal task under punishment only at the first and third reversals compared with both control participants and medicated patients with OCD, who had no deficit. Perseverative errors were correlated with OCD severity. On the probabilistic reversal task, unmedicated patients were only impaired at reversal, whereas medicated patients were impaired at both the learning and reversal stages. Computational modeling showed that the overall change was reduced feedback sensitivity in both OCD groups. Conclusions Both perseveration and increased shifting can be observed in OCD, depending on test conditions including the predictability of reinforcement. Perseveration was related to clinical severity and remediated by serotonergic medication.Peer reviewe

Early intervention for obsessive compulsive disorder : An expert consensus statement

© 2019 Elsevier B.V.and ECNP. All rights reserved.Obsessive-compulsive disorder (OCD) is common, emerges early in life and tends to run a chronic, impairing course. Despite the availability of effective treatments, the duration of untreated illness (DUI) is high (up to around 10 years in adults) and is associated with considerable suffering for the individual and their families. This consensus statement represents the views of an international group of expert clinicians, including child and adult psychiatrists, psychologists and neuroscientists, working both in high and low and middle income countries, as well as those with the experience of living with OCD. The statement draws together evidence from epidemiological, clinical, health economic and brain imaging studies documenting the negative impact associated with treatment delay on clinical outcomes, and supporting the importance of early clinical intervention. It draws parallels between OCD and other disorders for which early intervention is recognized as beneficial, such as psychotic disorders and impulsive-compulsive disorders associated with problematic usage of the Internet, for which early intervention may prevent the development of later addictive disorders. It also generates new heuristics for exploring the brain-based mechanisms moderating the ‘toxic’ effect of an extended DUI in OCD. The statement concludes that there is a global unmet need for early intervention services for OC related disorders to reduce the unnecessary suffering and costly disability associated with under-treatment. New clinical staging models for OCD that may be used to facilitate primary, secondary and tertiary prevention within this context are proposed.Peer reviewe

Mapping Compulsivity in the DSM-5 Obsessive Compulsive and Related Disorders: Cognitive Domains, Neural Circuitry, and Treatment.

Compulsions are repetitive, stereotyped thoughts and behaviors designed to reduce harm. Growing evidence suggests that the neurocognitive mechanisms mediating behavioral inhibition (motor inhibition, cognitive inflexibility) reversal learning and habit formation (shift from goal-directed to habitual responding) contribute toward compulsive activity in a broad range of disorders. In obsessive compulsive disorder, distributed network perturbation appears focused around the prefrontal cortex, caudate, putamen, and associated neuro-circuitry. Obsessive compulsive disorder-related attentional set-shifting deficits correlated with reduced resting state functional connectivity between the dorsal caudate and the ventrolateral prefrontal cortex on neuroimaging. In contrast, experimental provocation of obsessive compulsive disorder symptoms reduced neural activation in brain regions implicated in goal-directed behavioral control (ventromedial prefrontal cortex, caudate) with concordant increased activation in regions implicated in habit learning (presupplementary motor area, putamen). The ventromedial prefrontal cortex plays a multifaceted role, integrating affective evaluative processes, flexible behavior, and fear learning. Findings from a neuroimaging study of Pavlovian fear reversal, in which obsessive compulsive disorder patients failed to flexibly update fear responses despite normal initial fear conditioning, suggest there is an absence of ventromedial prefrontal cortex safety signaling in obsessive compulsive disorder, which potentially undermines explicit contingency knowledge and may help to explain the link between cognitive inflexibility, fear, and anxiety processing in compulsive disorders such as obsessive compulsive disorder

Serotonin depletion amplifies distinct human social emotions as a function of individual differences in personality

Funder: Gates Cambridge Trust; doi: https://doi.org/10.13039/501100005370Abstract: Serotonin is involved in a wide range of mental capacities essential for navigating the social world, including emotion and impulse control. Much recent work on serotonin and social functioning has focused on decision-making. Here we investigated the influence of serotonin on human emotional reactions to social conflict. We used a novel computerised task that required mentally simulating social situations involving unjust harm and found that depleting the serotonin precursor tryptophan—in a double-blind randomised placebo-controlled design—enhanced emotional responses to the scenarios in a large sample of healthy volunteers (n = 73), and interacted with individual differences in trait personality to produce distinctive human emotions. Whereas guilt was preferentially elevated in highly empathic participants, annoyance was potentiated in those high in trait psychopathy, with medium to large effect sizes. Our findings show how individual differences in personality, when combined with fluctuations of serotonin, may produce diverse emotional phenotypes. This has implications for understanding vulnerability to psychopathology, determining who may be more sensitive to serotonin-modulating treatments, and casts new light on the functions of serotonin in emotional processing