NMDA Receptors Subserve Persistent Neuronal Firing during Working Memory in Dorsolateral Prefrontal Cortex

SummaryNeurons in the primate dorsolateral prefrontal cortex (dlPFC) generate persistent firing in the absence of sensory stimulation, the foundation of mental representation. Persistent firing arises from recurrent excitation within a network of pyramidal Delay cells. Here, we examined glutamate receptor influences underlying persistent firing in primate dlPFC during a spatial working memory task. Computational models predicted dependence on NMDA receptor (NMDAR) NR2B stimulation, and Delay cell persistent firing was abolished by local NR2B NMDAR blockade or by systemic ketamine administration. AMPA receptors (AMPARs) contributed background depolarization to sustain network firing. In contrast, many Response cells were sensitive to AMPAR blockade and increased firing after systemic ketamine, indicating that models of ketamine actions should be refined to reflect neuronal heterogeneity. The reliance of Delay cells on NMDAR may explain why insults to NMDARs in schizophrenia or Alzheimer’s disease profoundly impair cognition

A computational psychiatry approach identifies how alpha-2A noradrenergic agonist Guanfacine affects feature-based reinforcement learning in the macaque

[EN] Noradrenaline is believed to support cognitive flexibility through the alpha 2A noradrenergic receptor (a2A-NAR) acting in prefrontal cortex. Enhanced flexibility has been inferred from improved working memory with the a2A-NA agonist Guanfacine. But it has been unclear whether Guanfacine improves specific attention and learning mechanisms beyond working memory, and whether the drug effects can be formalized computationally to allow single subject predictions. We tested and confirmed these suggestions in a case study with a healthy nonhuman primate performing a feature-based reversal learning task evaluating performance using Bayesian and Reinforcement learning models. In an initial dose-testing phase we found a Guanfacine dose that increased performance accuracy, decreased distractibility and improved learning. In a second experimental phase using only that dose we examined the faster feature-based reversal learning with Guanfacine with single-subject computational modeling. Parameter estimation suggested that improved learning is not accounted for by varying a single reinforcement learning mechanism, but by changing the set of parameter values to higher learning rates and stronger suppression of non-chosen over chosen feature information. These findings provide an important starting point for developing nonhuman primate models to discern the synaptic mechanisms of attention and learning functions within the context of a computational neuropsychiatry framework.This research was supported by grants from the Canadian Institutes of Health Research (CIHR), the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Ontario Ministry of Economic Development and Innovation (MEDI). We thank Dr. Hongying Wang for invaluable help with drug administration and animal careHassani, SA.; Oemisch, M.; Balcarras, M.; Westendorff, S.; Ardid-Ramírez, JS.; Van Der Meer, MA.; Tiesinga, P.... (2017). 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Self-Affirmation Improves Problem-Solving under Stress

High levels of acute and chronic stress are known to impair problem-solving and creativity on a broad range of tasks. Despite this evidence, we know little about protective factors for mitigating the deleterious effects of stress on problem-solving. Building on previous research showing that self-affirmation can buffer stress, we tested whether an experimental manipulation of self-affirmation improves problem-solving performance in chronically stressed participants. Eighty undergraduates indicated their perceived chronic stress over the previous month and were randomly assigned to either a self-affirmation or control condition. They then completed 30 difficult remote associate problem-solving items under time pressure in front of an evaluator. Results showed that self-affirmation improved problem-solving performance in underperforming chronically stressed individuals. This research suggests a novel means for boosting problem-solving under stress and may have important implications for understanding how self-affirmation boosts academic achievement in school settings. © 2013 Creswell et al

The statistical neuroanatomy of frontal networks in the macaque

We were interested in gaining insight into the functional properties of frontal networks based upon their anatomical inputs. We took a neuroinformatics approach, carrying out maximum likelihood hierarchical cluster analysis on 25 frontal cortical areas based upon their anatomical connections, with 68 input areas representing exterosensory, chemosensory, motor, limbic, and other frontal inputs. The analysis revealed a set of statistically robust clusters. We used these clusters to divide the frontal areas into 5 groups, including ventral-lateral, ventral-medial, dorsal-medial, dorsal-lateral, and caudal-orbital groups. Each of these groups was defined by a unique set of inputs. This organization provides insight into the differential roles of each group of areas and suggests a gradient by which orbital and ventral-medial areas may be responsible for decision-making processes based on emotion and primary reinforcers, and lateral frontal areas are more involved in integrating affective and rational information into a common framework

Effects of DSP4 and methylphenidate on spatial memory performance in rats

In this experiment, we have investigated the spatial memory performance of rats following a central noradrenaline depletion induced by three different doses of the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) and following administration of three different doses of methylphenidate (MPH). The rats were required to find food pellets hidden on a holeboard. The sole administration of DSP4 induced only minor cognitive deficits. However, the treatment with MPH increased the reference memory error, the impulsivity and the motor activity of the DSP4-treated rats. Since the noradrenergic terminals in a DSP4-treated rat are significantly reduced, the administration of MPH has little effect on the noradrenergic system and increases dopaminergic rather than noradrenergic activity, resulting in an imbalance with relatively high dopaminergic and low noradrenergic activities. It is suggested that a reduction of noradrenaline and an increase of dopamine induce ADHD-related deficits and that the depletion of noradrenaline is not sufficient for an appropriate rat model of ADHD

The effects of the neurotoxin DSP4 on spatial learning and memory in Wistar rats

The aim of the present study was to investigate the effect of DSP4-induced noradrenaline depletion on learning and memory in a spatial memory paradigm (holeboard). Since Harro et al. Brain Res 976:209–216 (2003) have demonstrated that short-term effects of DSP4 administration include both noradrenaline depletion and changes in dopamine and its metabolites—with the latter vanishing within 4 weeks after the neurotoxic lesion—the behavioural effects observed immediately after DSP4 administration cannot solely be related to noradrenaline. In the present study, spatial learning, reference memory and working memory were therefore assessed 5–10 weeks after DSP4 administration. Our results suggest that the administration of DSP4 did not lead to changes in spatial learning and memory when behavioural assessment was performed after a minimum of 5 weeks following DSP4. This lack of changes in spatial behaviour suggests that the role of noradrenaline regarding these functions may be limited. Future studies will therefore have to take into account the time-course of neurotransmitter alterations and behavioural changes following DSP4 administration

Dopaminergic modulation of appetitive trace conditioning: the role of D1 receptors in medial prefrontal cortex

Rationale: Trace conditioning may provide a behavioural model suitable to examine the maintenance of ‘on line’ information and its underlying neural substrates. Objectives: Experiment la was run to establish trace conditioning in a shortened procedure which would be suitable to test the effects of dopamine (DA) D1 receptor agents administered by microinjection directly into the brain. Experiment lb examined the effects of the DA D1 agonist SKF81297 and the DA D1 antagonist SCH23390 following systemic administration in pre-trained animals. Experiment 2 went on to test the effects of systemically administered SKF81297 on the acquisition of trace conditioning. In experiment 3, SKF81297 was administered directly in prelimbic (PL) and infralimbic (IL) sub-regions of medial prefrontal cortex (mPFC) to compare the role of different mPFC sub-regions. Results: Whilst treatment with SCH23390 impaired motor responding and/or motivation, SKF81297 had relatively little effect in the pre-trained animals tested in experiment 1b. However, systemic SKF81297 depressed the acquisition function at the 2-s trace interval in experiment 2. Similarly, in experiment 3, SKF81297 (0.1 μg in 1.0 μl) microinjected into either PL or IL mPFC impaired appetitive conditioning at the 2-s trace interval. Conclusions: Impaired trace conditioning under SKF81297 is likely to be mediated in part (but not exclusively) within the IL and PL mPFC sub-regions. The finding that trace conditioning was impaired rather than enhanced under SKF81297 provides further evidence for the inverse U-function which has been suggested to be characteristic of mPFC DA function

Mindfulness-based interventions for young offenders: a scoping review

Youth offending is a problem worldwide. Young people in the criminal justice system have frequently experienced adverse childhood circumstances, mental health problems, difficulties regulating emotions and poor quality of life. Mindfulness-based interventions can help people manage problems resulting from these experiences, but their usefulness for youth offending populations is not clear. This review evaluated existing evidence for mindfulness-based interventions among such populations. To be included, each study used an intervention with at least one of the three core components of mindfulness-based stress reduction (breath awareness, body awareness, mindful movement) that was delivered to young people in prison or community rehabilitation programs. No restrictions were placed on methods used. Thirteen studies were included: three randomized controlled trials, one controlled trial, three pre-post study designs, three mixed-methods approaches and three qualitative studies. Pooled numbers (n = 842) comprised 99% males aged between 14 and 23. Interventions varied so it was not possible to identify an optimal approach in terms of content, dose or intensity. Studies found some improvement in various measures of mental health, self-regulation, problematic behaviour, substance use, quality of life and criminal propensity. In those studies measuring mindfulness, changes did not reach statistical significance. Qualitative studies reported participants feeling less stressed, better able to concentrate, manage emotions and behaviour, improved social skills and that the interventions were acceptable. Generally low study quality limits the generalizability of these findings. Greater clarity on intervention components and robust mixed-methods evaluation would improve clarity of reporting and better guide future youth offending prevention programs

Paradoxical reversal learning enhancement by stress or prefrontal cortical damage: rescue with BDNF.

Stress affects various forms of cognition. We found that moderate stress enhanced late reversal learning in a mouse touchscreen-based choice task. Ventromedial prefrontal cortex (vmPFC) lesions mimicked the effect of stress, whereas orbitofrontal and dorsolateral striatal lesions impaired reversal. Stress facilitation of reversal was prevented by BDNF infusion into the vmPFC. These findings suggest a mechanism by which stress-induced vmPFC dysfunction disinhibits learning by alternate (for example, striatal) systems