Impaired Sensorimotor Adaption in Schizophrenia in Comparison to Age-Matched and Elderly Controls

<b><i>Background:</i></b> The “cognitive dysmetria hypothesis” of schizophrenia proposes a disrupted communication between the cerebellum and cerebral cortex, resulting in sensorimotor and cognitive symptoms. Sensorimotor adaptation relies strongly on the function of the cerebellum. <b><i>Objectives:</i></b> This study investigated whether sensorimotor adaptation is reduced in schizophrenia compared with age-matched and elderly healthy controls. <b><i>Methods:</i></b> Twenty-nine stably treated patients with schizophrenia, 30 age-matched, and 30 elderly controls were tested in three motor adaptation tasks in which visual movement feedback was unexpectedly altered. In the “rotation adaptation task” the perturbation consisted of a rotation (30° clockwise), in the “gain adaptation task” the extent of the movement feedback was reduced (by a factor of 0.7) and in the “vertical reversal task,” up- and downward pen movements were reversed by 180°. <b><i>Results:</i></b> Patients with schizophrenia adapted to the perturbations, but their movement times and errors were substantially larger than controls. Unexpectedly, the magnitude of adaptation was significantly smaller in schizophrenia than elderly participants. The impairment already occurred during the first adaptation trials, pointing to a decline in explicit strategy use. Additionally, post-adaptation aftereffects provided strong evidence for impaired implicit adaptation learning. Both negative and positive schizophrenia symptom severities were correlated with indices of the amount of adaptation and its aftereffects. <b><i>Conclusions:</i></b> Both explicit and implicit components of sensorimotor adaptation learning were reduced in patients with schizophrenia, adding to the evidence for a role of the cerebellum in the pathophysiology of schizophrenia. Elderly individuals outperformed schizophrenia patients in the adaptation learning tasks.

Implicit adaptation to mirror-reversal is in the correct coordinate system but the wrong direction

Learning in visuomotor adaptation tasks is the result of both explicit and implicit processes. Explicit processes, operationalized as re-aiming an intended movement to a new goal, account for a significant proportion of learning. However, implicit processes, operationalized as error-dependent learning that gives rise to aftereffects, appear to be highly constrained. The limitations of implicit learning are highlighted in the mirror-reversal task, where implicit corrections act in opposition to performance. This is surprising given the mirror-reversal task has been viewed as emblematic of implicit learning. One potential issue not being considered in these studies is that both explicit and implicit processes were allowed to operate concurrently, which may interact, potentially in opposition. Therefore, we sought to further characterized implicit learning in a mirror-reversal task with a clamp design to isolate implicit learning from explicit strategies. We confirmed that implicit adaptation is in the wrong direction for mirror-reversal and operates as if the perturbation were a rotation, and only showed a moderate attenuation after three days of training. This result raised the question of whether implicit adaptation blindly operates as though perturbations were a rotation. In a separate experiment, which directly compared a mirror-reversal and a rotation, we found that implicit adaptation operates in a proper coordinate system for different perturbations: adaptation to a mirror-reversal and rotational perturbation is more consistent with Cartesian and polar coordinate systems, respectively. It remains an open question why implicit process would be flexible to the coordinate system of a perturbation but continue to be directed inappropriately.

Characterization of striatal dopamine projections across striatal subregions in behavioral flexibility

Behavioral flexibility is key to survival in a dynamic environment. While flexible, goal-directed behaviors are initially dependent on dorsomedial striatum, they become dependent on lateral striatum with extended training as behaviors become inflexible. Similarly, dopamine release shifts from ventromedial to lateral striatum across learning, and impairment of lateral dopamine release disrupts habitual, inflexible responding. This raises the possibility that lateral dopamine release is a causative mechanism in establishing inflexible behaviors late in training, though this has not been directly tested. Here, we utilized optogenetics to activate dopamine terminals in dorsal medial (DMS), dorsal lateral (DLS), and ventral (NAc) striatum in DATcre mice to determine how specific dopamine subpopulations impact behavioral flexibility. Mice performed a reversal task in which they self-stimulated DMS, DLS, or NAc dopamine terminals by pressing one of two levers before action-outcome lever contingencies were reversed. Consistent with presumed ventromedial/lateral striatal function, we found that mice self-stimulating ventromedial dopamine terminals rapidly reversed lever preference following contingency reversal, while mice self-stimulating dopamine terminals in DLS showed impaired reversal learning. These impairments were characterized by more regressive errors and reliance on lose-stay strategies following reversal, suggesting reward insensitivity and overreliance on previously learned actions. This study supports a model of striatal function in which dorsomedial dopamine facilitates goal-directed responding, and dorsolateral dopamine release is a key mechanism in supporting the transition toward inflexible behaviors.

Prepubertal ovariectomy alters dorsomedial striatum indirect pathway neuron excitability and explore/exploit balance in female mice

Decision-making circuits are modulated across life stages (e.g. juvenile, adolescent, or adult)—as well as on the shorter timescale of reproductive cycles in females—to meet changing environmental and physiological demands. Ovarian hormonal modulation of relevant neural circuits is a potential mechanism by which behavioral flexibility is regulated in females. Here we examined the influence of prepubertal ovariectomy (pOVX) versus sham surgery on performance in an odor-based multiple choice reversal task. We observed that pOVX females made different types of errors during reversal learning compared to sham surgery controls. Using reinforcement learning models fit to trial-by-trial behavior, we found that pOVX females exhibited lower inverse temperature parameter (β) compared to sham females. These findings suggest that OVX females solve the reversal task using a more exploratory choice policy, whereas sham females use a more exploitative policy prioritizing estimated high value options. To seek a neural correlate of this behavioral difference, we performed whole-cell patch clamp recordings within the dorsomedial striatum (DMS), a region implicated in regulating action selection and explore/exploit choice policy. We found that the intrinsic excitability of dopamine receptor type 2 (D2R) expressing indirect pathway spiny projection neurons (iSPNs) was significantly higher in pOVX females compared to both unmanipulated and sham surgery females. Finally, to test whether mimicking this increase in iSPN excitability could recapitulate the pattern of reversal task behavior observed in pOVX females, we chemogenetically activated DMS D2R(+) neurons within intact female mice. We found that chemogenetic activation increased exploratory choice during reversal, similar to the pattern we observed in pOVX females. Together, these data suggest that pubertal status may influence explore/exploit balance in females via the modulation of iSPN intrinsic excitability within the DMS.

Implicit adaptation to mirror-reversal is in the correct coordinate system but the wrong direction

Learning in visuomotor adaptation tasks is the result of both explicit and implicit processes. Explicit processes, operationalized as re-aiming an intended movement to a new goal, account for the lion's share of learning while implicit processes, operationalized as error-dependent learning that gives rise to aftereffects, appear to be highly constrained. The limitations of implicit learning are highlighted in the mirror-reversal task, where implicit corrections act in opposition to performance. This is surprising given the mirror-reversal task has been viewed as emblematic of implicit learning. One potential confound of these studies is that both explicit and implicit processes were allowed to operate concurrently, which may interact, potentially in opposition. Therefore, we sought to further characterized implicit learning in a mirror-reversal task with a clamp design to isolate implicit learning from explicit strategies. We confirmed that implicit adaptation is in the wrong direction for mirror-reversal and operates as if the perturbation were a rotation, and only showed a moderate attenuation after three days of training. This result raised the question of whether implicit adaptation blindly operates as though perturbations were a rotation. In a separate experiment, which directly compared a mirror-reversal and a rotation, we found that implicit adaptation operates in a proper coordinate system for different perturbations: adaptation to a mirror-reversal and rotational perturbation is more consistent with Cartesian and polar coordinate systems, respectively. It remains an open question why implicit process would be flexible to the coordinate system of a perturbation but continue to be directed inappropriately.

Behavioral measures of impulsivity and compulsivity in adolescents with nonsuicidal self-injury

Background Nonsuicidal self-injury (NSSI) is prevalent among adolescents and research is needed to clarify the mechanisms which contribute to the behavior. Here, the authors relate behavioral neurocognitive measures of impulsivity and compulsivity to repetitive and sporadic NSSI in a community sample of adolescents. Methods Computerized laboratory tasks (Affective Go/No-Go, Cambridge Gambling Task, and Probabilistic Reversal Task) were used to evaluate cognitive performance. Participants were adolescents aged 15 to 17 with (n = 50) and without (n = 190) NSSI history, sampled from the ROOTS project which recruited adolescents from secondary schools in Cambridgeshire, UK. NSSI was categorized as sporadic (1-3 instances per year) or repetitive (4 or more instances per year). Analyses were carried out in a series of linear and negative binomial regressions, controlling for age, gender, intelligence, and recent depressive symptoms. Results Adolescents with lifetime NSSI, and repetitive NSSI specifically, made significantly more perseverative errors on the Probabilistic Reversal Task and exhibited significantly lower quality of decision making on the Cambridge Gambling Task compared to no-NSSI controls. Those with sporadic NSSI did not significantly differ from no-NSSI controls on task performance. NSSI was not associated with behavioral measures of impulsivity. Conclusions Repetitive NSSI is associated with increased behavioral compulsivity and disadvantageous decision making, but not with behavioral impulsivity. Future research should continue to investigate how neurocognitive phenotypes contribute to the onset and maintenance of NSSI, and determine whether compulsivity and addictive features of NSSI are potential targets for treatment.

Neurogenesis-mediated forgetting of complex paired-associates memories

The hippocampus is a critical structure involved in many forms of learning and memory. It is also one of the only regions in the adult mammalian brain that continues to generate new neurons throughout adulthood. This process of adult neurogenesis may increase the plasticity of the hippocampus which could be beneficial for learning but has also been demonstrated to decrease the stability of previously acquired memories. Here we test whether increased production of new neurons following the formation of a gradually acquired paired-associates task will result in forgetting of this type of memory. We trained mice in a touchscreen-based object/location task and then increased neurogenesis using voluntary exercise. Our results indicate that mice with increased neurogenesis show poor recall of the previously established memory. When subsequently exposed to a reversal task we also show that mice with increased neurogenesis require fewer correction trials to acquire the new task contingencies. This suggests that prior forgetting reduces perseveration on the now outdated memory. Together our results add to a growing body of literature which indicates the important role of adult neurogenesis in destabilizing previously acquired memories to allow for flexible encoding of new memories.

Interspecific two-dimensional visual discrimination of faces in horses (Equus caballus)

In social animals, recognizing conspecifics and distinguishing them from other animal species is certainly important. We hypothesize, as demonstrated in other species of ungulates, that horses are able to discriminate between the faces of conspecifics and the faces of other domestic species (cattle, sheep, donkeys and pigs). Our hypothesis was tested by studying inter-and intra-specific visual discrimination abilities in horses through a two-way instrumental conditioning task (discrimination and reversal learning), using two-dimensional images of faces as discriminative stimuli and food as a positive reward. Our results indicate that 8 out of 10 horses were able to distinguish between two-dimensional images of the faces of horses and images showing the faces of other species. A similar performance was obtained in the reversal task. The horses’ ability to learn by discrimination is therefore comparable to other ungulates. Horses also showed the ability to learn a reversal task. However, these results were obtained regardless of the images the tested horses were exposed to. We therefore conclude that horses can discriminate between two dimensional images of conspecifics and two dimensional images of different species, however in our study, they were not able to make further subcategories within each of the two categories. Despite the fact that two dimensional images of animals could be treated differently from two dimensional images of non-social stimuli, our results beg the question as to whether a two-dimensional image can replace the real animal in cognitive tests.