Dynamic behaviour restructuring mediates dopamine-dependent credit assignment.

Animals exhibit a diverse behavioural repertoire when exploring new environments and can learn which actions or action sequences produce positive outcomes. Dopamine release after encountering a reward is critical for reinforcing reward-producing actions1-3. However, it has been challenging to understand how credit is assigned to the exact action that produced the dopamine release during continuous behaviour. Here we investigated this problem in mice using a self-stimulation paradigm in which specific spontaneous movements triggered optogenetic stimulation of dopaminergic neurons. Dopamine self-stimulation rapidly and dynamically changes the structure of the entire behavioural repertoire. Initial stimulations reinforced not only the stimulation-producing target action, but also actions similar to the target action and actions that occurred a few seconds before stimulation. Repeated pairings led to a gradual refinement of the behavioural repertoire to home in on the target action. Reinforcement of action sequences revealed further temporal dependencies of refinement. Action pairs spontaneously separated by long time intervals promoted a stepwise credit assignment, with early refinement of actions most proximal to stimulation and subsequent refinement of more distal actions. Thus, a retrospective reinforcement mechanism promotes not only reinforcement, but also gradual refinement of the entire behavioural repertoire to assign credit to specific actions and action sequences that lead to dopamine release.

Explicit knowledge of task structure is a primary determinant of human model-based action.

Explicit information obtained through instruction profoundly shapes human choice behaviour. However, this has been studied in computationally simple tasks, and it is unknown how model-based and model-free systems, respectively generating goal-directed and habitual actions, are affected by the absence or presence of instructions. We assessed behaviour in a variant of a computationally more complex decision-making task, before and after providing information about task structure, both in healthy volunteers and in individuals suffering from obsessive-compulsive or other disorders. Initial behaviour was model-free, with rewards directly reinforcing preceding actions. Model-based control, employing predictions of states resulting from each action, emerged with experience in a minority of participants, and less in those with obsessive-compulsive disorder. Providing task structure information strongly increased model-based control, similarly across all groups. Thus, in humans, explicit task structural knowledge is a primary determinant of model-based reinforcement learning and is most readily acquired from instruction rather than experience.

Childhood adversities and the comorbidity between mood and general medical disorders in adults: Results from the WHO World Mental Health Survey Portugal.

OBJECTIVE: Childhood adversities have been linked to poor health outcomes in adults, including both mood and general medical disorders. Here we tested the hypothesis that childhood adversities specifically increase the risk of comorbidity between mood and general medical disorders, rather than increasing the risk of either one independently. METHODS: Mood disorders (DSM-IV major depressive, dysthymic and bipolar disorders), childhood adversities and general medical disorders were assessed in 2060 adults in the WHO World Mental Health Survey Portugal. Discrete-time survival analyses were used to investigate the association between mood disorders and subsequent first-onset general medical disorders and between general medical disorders and subsequent first-onset mood disorders, in adults. Discrete-time survival and multinomial regression analyses were used to test the influence of childhood adversities on the comorbidity between mood disorders and general medical disorders. Anxiety disorders were used as a psychiatric control. RESULTS: Adult-onset mood disorders were found to precede the onset of diabetes (OR:1.8; 95% CI:1.2-2.9), arthritis (OR:1.6; 95% CI:1.1-2.3) and seasonal allergies (OR:1.6; 95% CI:1.1-2.5) while adult-onset hypertension was found to precede the onset of mood disorders (OR:1.7; 95% CI:1.2-2.6). Maladaptive family functioning (abuse, neglect and parental maladjustment), was associated with mood disorders (OR:1.5; 95% CI:1.2-1.9), hypertension (OR:1.4; 95% CI:1.1-1.7), arthritis (OR:1.3; 95% CI:1.0-1.6) and seasonal allergies (OR:1.5; 95% CI:1.1-2.0) in adulthood. Finally, the effect of maladaptive family functioning in predicting comorbid mood disorders and arthritis significantly differed from its effect in predicting only arthritis (p â€‹= â€‹0.01), which was not observed for other comorbidities. Maladaptive family functioning further predicted comorbid anxiety disorders and hypertension. CONCLUSION: Childhood adversities may be a specific risk factor for comorbid mood disorders and arthritis in adults.

Dopamine neuron activity before action initiation gates and invigorates future movements.

Deciding when and whether to move is critical for survival. Loss of dopamine neurons (DANs) of the substantia nigra pars compacta (SNc) in patients with Parkinson's disease causes deficits in movement initiation and slowness of movement. The role of DANs in self-paced movement has mostly been attributed to their tonic activity, whereas phasic changes in DAN activity have been linked to reward prediction. This model has recently been challenged by studies showing transient changes in DAN activity before or during self-paced movement initiation. Nevertheless, the necessity of this activity for spontaneous movement initiation has not been demonstrated, nor has its relation to initiation versus ongoing movement been described. Here we show that a large proportion of SNc DANs, which did not overlap with reward-responsive DANs, transiently increased their activity before self-paced movement initiation in mice. This activity was not action-specific, and was related to the vigour of future movements. Inhibition of DANs when mice were immobile reduced the probability and vigour of future movements. Conversely, brief activation of DANs when mice were immobile increased the probability and vigour of future movements. Manipulations of dopamine activity after movement initiation did not affect ongoing movements. Similar findings were observed for the initiation and execution of learned action sequences. These findings causally implicate DAN activity before movement initiation in the probability and vigour of future movements.

Toxoplasma-induced changes in host risk behaviour are independent of parasite-derived AaaH2 tyrosine hydroxylase.

Toxoplasma gondii infects a broad range of hosts and can establish chronic infections with the formation of brain cysts. Infected animals show altered risk behaviour which has been suggested to increase capture probability of hosts, and thus enhance parasite transmission. It has been proposed that the ability of Toxoplasma cysts to secrete tyrosine hydroxylase could mediate these behavioural alterations. We tested the involvement of secreted tyrosine hydroxylase, coded by the parasite AaaH2 gene, in the development of alterations in mouse behaviour, by generating an AaaH2 deletion mutant parasite strain and testing its influence on behaviour. We found that both mice infected with wild type or AaaH2 mutant strains showed changes in risk behaviour. We confirmed these findings using factor analysis of the behaviour, which revealed that behavioural changes happened along a single dimension, and were observed in both infected groups. Furthermore, we developed a new behavioural paradigm in which animals are unpredictably trapped, and observed that both groups of infected animals perceive trapping but fail to adjust their behaviour to avoid further trapping. These results demonstrate that parasite-secreted AaaH2 TH is neither necessary for the generation of risky behaviour nor for the increased trappability observed during chronic Toxoplasma infection.

The Spatiotemporal Organization of the Striatum Encodes Action Space.

Activity in striatal direct- and indirect-pathway spiny projection neurons (SPNs) is critical for proper movement. However, little is known about the spatiotemporal organization of this activity. We investigated the spatiotemporal organization of SPN ensemble activity in mice during self-paced, natural movements using microendoscopic imaging. Activity in both pathways showed predominantly local but also some long-range correlations. Using a novel approach to cluster and quantify behaviors based on continuous accelerometer and video data, we found that SPN ensembles active during specific actions were spatially closer and more correlated overall. Furthermore, similarity between different actions corresponded to the similarity between SPN ensemble patterns, irrespective of movement speed. Consistently, the accuracy of decoding behavior from SPN ensemble patterns was directly related to the dissimilarity between behavioral clusters. These results identify a predominantly local, but not spatially compact, organization of direct- and indirect-pathway SPN activity that maps action space independently of movement speed.

A Perspective on Wearable Sensor Measurements and Data Science for Parkinson's Disease.

Miniaturized and wearable sensor-based measurements enable the assessment of Parkinson's disease (PD) motor-related features like never before and hold great promise as non-invasive biomarkers for early and accurate diagnosis, and monitoring the progression of PD. High-fidelity human movement reconstruction and simulation can already be conducted in a clinical setting with increasingly precise and affordable motion technology enabling access to high-quality labeled data on patients' subcomponents of movement (kinematics and kinetics). At the same time, body-worn sensors now allow us to extend some quantitative movement-related measurements to patients' daily living activities. This era of patient movement "cognification" is bringing us previously inaccessible variables that encode patients' movement, and that, together with measures from clinical examinations, poses new challenges in data analysis. We present herein examples of the application of an unsupervised methodology to classify movement behavior in healthy individuals and patients with PD where no specific knowledge on the type of behaviors recorded is needed. We are most certainly leaving the early stage of the exponential curve that describes the current technological evolution and soon will be entering its steep ascent. But there is already a benefit to be derived from current motion technology and sophisticated data science methods to objectively measure parkinsonian impairments.

Chronic Toxoplasma infection modifies the structure and the risk of host behavior.

The intracellular parasite Toxoplasma has an indirect life cycle, in which felids are the definitive host. It has been suggested that this parasite developed mechanisms for enhancing its transmission rate to felids by inducing behavioral modifications in the intermediate rodent host. For example, Toxoplasma-infected rodents display a reduction in the innate fear of predator odor. However, animals with Toxoplasma infection acquired in the wild are more often caught in traps, suggesting that there are manipulations of intermediate host behavior beyond those that increase predation by felids. We investigated the behavioral modifications of Toxoplasma-infected mice in environments with exposed versus non-exposed areas, and found that chronically infected mice with brain cysts display a plethora of behavioral alterations. Using principal component analysis, we discovered that most of the behavioral differences observed in cyst-containing animals reflected changes in the microstructure of exploratory behavior and risk/unconditioned fear. We next examined whether these behavioral changes were related to the presence and distribution of parasitic cysts in the brain of chronically infected mice. We found no strong cyst tropism for any particular brain area but found that the distribution of Toxoplasma cysts in the brain of infected animals was not random, and that particular combinations of cyst localizations changed risk/unconditioned fear in the host. These results suggest that brain cysts in animals chronically infected with Toxoplasma alter the fine structure of exploratory behavior and risk/unconditioned fear, which may result in greater capture probability of infected rodents. These data also raise the possibility that selective pressures acted on Toxoplasma to broaden its transmission between intermediate predator hosts, in addition to felid definitive hosts.

Revealing the structural origin of the redox-Bohr effect: the first solution structure of a cytochrome from Geobacter sulfurreducens.

Gs (Geobacter sulfurreducens) can transfer electrons to the exterior of its cells, a property that makes it a preferential candidate for the development of biotechnological applications. Its genome encodes over 100 cytochromes and, despite their abundance and key functional roles, to date there is no structural information for these proteins in solution. The trihaem cytochrome PpcA might have a crucial role in the conversion of electronic energy into protonmotive force, a fundamental step for ATP synthesis in the presence of extracellular electron acceptors. In the present study, 15N-labelled PpcA was produced and NMR spectroscopy was used to determine its solution structure in the fully reduced state, its backbone dynamics and the pH-dependent conformational changes. The structure obtained is well defined, with an average pairwise rmsd (root mean square deviation) of 0.25 Å (1 Å=0.1 nm) for the backbone atoms and 0.99 Å for all heavy atoms, and constitutes the first solution structure of a Gs cytochrome. The redox-Bohr centre responsible for controlling the electron/proton transfer was identified, as well as the putative interacting regions between PpcA and its redox partners. The solution structure of PpcA will constitute the foundation for studies aimed at mapping out in detail these interacting regions.

Backbone, side chain and heme resonance assignments of the triheme cytochrome PpcA from Geobacter sulfurreducens.

Gene knock-out studies on Geobacter sulfurreducens cells showed that the periplasmic triheme cytochrome PpcA is involved in respiratory pathways leading to the extracellular reduction of Fe(III) and U(VI) oxides. The crucial role of this protein in bridging the electron transfer between the cytoplasm and cell exterior was further supported by proteomics studies. In comparison with non-heme proteins, the presence of numerous proton-containing groups in the heme groups causes additional challenges to the full protein assignment and structure calculation. Here, we report the complete assignment of the heme proton signals together with the (1)H and (15)N backbone and side chain assignments of the reduced form of PpcA.

Redox linked conformational changes in cytochrome c3 from Desulfovibrio desulfuricans ATCC 27774.

Cytochrome c3 from Desulfovibrio desulfuricans ATCC 27774 appears to be capable of receiving two protons and two electrons from hydrogenase for transport to the membrane, and converting electronic energy into proton motive force. Detailed studies of the mechanism require control both of the redox state and of the protonation state of the protein; hence, structure determination of the protein in solution by NMR is the preferred method. This work compares the structures of the protonated protein in the fully oxidized and fully reduced states as a first step toward elucidating the pH-dependent and redox-state-dependent conformational changes that drive the energy transduction. These high-resolution structures revealed significant localized differences upon change of redox state, even though the global folds of the two families of structures are similar. There are concerted redox-linked motions within the protein that bring E61 and K75 closer to heme II in the oxidized form. This is consistent with an electrostatically driven movement that may provide an important contribution to the previously measured positive cooperativity between hemes I and II. No significant conformational changes were observed that might be related to redox−Bohr effects; the families of structures represent mainly protonated forms, and therefore, pH dependence should not play a major role in the observed structural rearrangements.

The solution structure of a tetraheme cytochrome from Shewanella frigidimarina reveals a novel family structural motif.

The bacteria belonging to the genus Shewanella are facultative anaerobes that utilize a variety of terminal electron acceptors which includes soluble and insoluble metal oxides. The tetraheme c-type cytochrome isolated during anaerobic growth of Shewanella frigidimarina NCIMB400 ( Sfc) contains 86 residues and is involved in the Fe(III) reduction pathways. Although the functional properties of Sfc redox centers are quite well described, no structures are available for this protein. In this work, we report the solution structure of the reduced form of Sfc. The overall fold is completely different from those of the tetraheme cytochromes c 3 and instead has similarities with the tetraheme cytochrome recently isolated from Shewanella oneidensis ( Soc). Comparison of the tetraheme cytochromes from Shewanella shows a considerable diversity in their primary structure and heme reduction potentials, yet they have highly conserved heme geometry, as is the case for the family of tetraheme cytochromes isolated from Desulfovibrio spp.