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Human brain imaging research using functional MRI (fMRI) has uncovered flexible variations in the functional connectivity between brain regions. While some of this variability likely arises from the pattern of information flow through circuits, it may also be influenced by rapid changes in effective synaptic strength at the molecular level, a phenomenon called Dynamic Network Connectivity (DNC) discovered in non-human primate circuits. These neuromodulatory molecular mechanisms are found in layer III of the macaque dorsolateral prefrontal cortex (dlPFC), the site of the microcircuits shown by Goldman-Rakic to be critical for working memory. This research has shown that the neuromodulators acetylcholine, norepinephrine, and dopamine can rapidly change the strength of synaptic connections in layer III dlPFC by (1) modifying the depolarization state of the post-synaptic density needed for NMDA receptor neurotransmission and (2) altering the open state of nearby potassium channels to rapidly weaken or strengthen synaptic efficacy and the strength of persistent neuronal firing. Many of these actions involve increased cAMP-calcium signaling in dendritic spines, where varying levels can coordinate the arousal state with the cognitive state. The current review examines the hypothesis that some of the dynamic changes in correlative strength between cortical regions observed in human fMRI studies may arise from these molecular underpinnings, as has been seen when pharmacological agents or genetic alterations alter the functional connectivity of the dlPFC consistent with the macaque physiology. These DNC mechanisms provide essential flexibility but may also confer vulnerability to malfunction when dysregulated in cognitive disorders. 

Sustained cognitive deficits are a common and debilitating feature of “long COVID”, but currently there are no FDA-approved treatments. The cognitive functions of the dorsolateral prefrontal cortex (dlPFC) are the most consistently afflicted by long COVID, including deficits in working memory, motivation, and executive functioning. COVID-19 infection greatly increases kynurenic acid (KYNA) and glutamate carboxypeptidase II (GCPII) in brain, both of which can be particularly deleterious to PFC function. KYNA blocks both NMDA and nicotinic-alpha-7 receptors, the two receptors required for dlPFC neurotransmission, and GCPII reduces mGluR3 regulation of cAMP-calcium-potassium channel signaling, which weakens dlPFC network connectivity and reduces dlPFC neuronal firing. Two agents approved for other indications may be helpful in restoring dlPFC physiology: the antioxidant N-acetyl cysteine inhibits the production of KYNA, and the α2A-adrenoceptor agonist guanfacine regulates cAMP-calcium-potassium channel signaling in dlPFC and is also anti-inflammatory. Thus, these agents may be helpful in treating the cognitive symptoms of long COVID. 

Informal mathematics learning has been far less studied than informal science learning – but youth can experience and learn about mathematics in their homes and communities. “Math walks” where students learn about how mathematics appears in the world around them, and have the opportunity to create their own math walk stops in their communities, can be a particularly powerful approach to informal mathematics learning. This study implemented an explanatory sequential mixed-method research design to investigate the impact of problem-posing activities in the math walks program on high school students' mathematical outcomes. The program was implemented during the pandemic and was modified to an online program where students met with instructors via online meetings. The researchers analyzed students' problem-posing work, surveyed students' interest in mathematics before and after the program, and compared the complexity of self-generated problems in pre- and post-assessments and different learning activities in the program. The results of the study suggest that students posed more complex problems in free problem-posing activities than in semi-structured problem-posing. Students also posed more complex problems in the post-survey than in the pre-survey. Students' mathematical dispositions did not significantly change from the pre-survey to post-survey, but the qualitative analysis showed that they began thinking more deeply, asking questions, and connecting school content to real-world scenarios. This study provides evidence that the math walks program is an effective approach to informal mathematics learning. The program was successful in helping students develop problem-posing skills and connect mathematical concepts to the world around them. Overall, “math walks” provide a powerful opportunity for informal mathematics learning. 

ImportanceThe risk of mental disorders is consistently associated with variants inCACNA1C(L-type calcium channel Cav1.2) but it is not known why these channels are critical to cognition, and whether they affect the layer III pyramidal cells in the dorsolateral prefrontal cortex that are especially vulnerable in cognitive disorders. ObjectiveTo examine the molecular mechanisms expressed in layer III pyramidal cells in primate dorsolateral prefrontal cortices. Design, Setting, and ParticipantsThe design included transcriptomic analyses from human and macaque dorsolateral prefrontal cortex, and connectivity, protein expression, physiology, and cognitive behavior in macaques. The research was performed in academic laboratories at Yale, Harvard, Princeton, and the University of Pittsburgh. As dorsolateral prefrontal cortex only exists in primates, the work evaluated humans and macaques. Main Outcomes and MeasuresOutcome measures included transcriptomic signatures of human and macaque pyramidal cells, protein expression and interactions in layer III macaque pyramidal cells using light and electron microscopy, changes in neuronal firing during spatial working memory, and working memory performance following pharmacological treatments. ResultsLayer III pyramidal cells in dorsolateral prefrontal cortex coexpress a constellation of calcium-related proteins, delineated byCALB1(calbindin), and high levels ofCACNA1C(Cav1.2),GRIN2B(NMDA receptor GluN2B), andKCNN3(SK3 potassium channel), concentrated in dendritic spines near the calcium-storing smooth endoplasmic reticulum. L-type calcium channels influenced neuronal firing needed for working memory, where either blockade or increased drive by β1-adrenoceptors, reduced neuronal firing by a mean (SD) 37.3% (5.5%) or 40% (6.3%), respectively, the latter via SK potassium channel opening. An L-type calcium channel blocker or β1-adrenoceptor antagonist protected working memory from stress. Conclusions and RelevanceThe layer III pyramidal cells in the dorsolateral prefrontal cortex especially vulnerable in cognitive disorders differentially express calbindin and a constellation of calcium-related proteins including L-type calcium channels Cav1.2 (CACNA1C), GluN2B-NMDA receptors (GRIN2B), and SK3 potassium channels (KCNN3), which influence memory-related neuronal firing. The finding that either inadequate or excessive L-type calcium channel activation reduced neuronal firing explains why either loss- or gain-of-function variants inCACNA1Cwere associated with increased risk of cognitive disorders. The selective expression of calbindin in these pyramidal cells highlights the importance of regulatory mechanisms in neurons with high calcium signaling, consistent with Alzheimer tau pathology emerging when calbindin is lost with age and/or inflammation.