Stress and Inflammation Target Dorsolateral Prefrontal Cortex Function: Neural Mechanisms Underlying Weakened Cognitive Control.

Most mental disorders involve dysfunction of the dorsolateral prefrontal cortex (dlPFC), a recently evolved brain region that subserves working memory, abstraction, and the thoughtful regulation of attention, action, and emotion. For example, schizophrenia, depression, long COVID, and Alzheimer's disease are all associated with dlPFC dysfunction, with neuropathology often being focused in layer III. The dlPFC has extensive top-down projections, e.g., to the posterior association cortices to regulate attention and to the subgenual cingulate cortex via the rostral and medial PFC to regulate emotional responses. However, the dlPFC is particularly dependent on arousal state and is very vulnerable to stress and inflammation, which are etiological and/or exacerbating factors for most mental disorders. The cellular mechanisms by which stress and inflammation impact the dlPFC are a topic of current research and are summarized in this review. For example, the layer III dlPFC circuits that generate working memory-related neuronal firing have unusual neurotransmission, depending on NMDA receptor and nicotinic α7 receptor actions that are blocked under inflammatory conditions by kynurenic acid. These circuits also have unusual neuromodulation, with the molecular machinery to magnify calcium signaling in spines needed to support persistent firing, which must be tightly regulated to prevent toxic calcium actions. Stress rapidly weakens layer III connectivity by driving feedforward calcium-cAMP (cyclic adenosine monophosphate) opening of potassium channels on spines. This is regulated by postsynaptic noradrenergic α2A adrenergic receptor and mGluR3 (metabotropic glutamate receptor 3) signaling but dysregulated by inflammation and/or chronic stress exposure, which contribute to spine loss. Treatments that strengthen the dlPFC via pharmacological (the α2A adrenergic receptor agonist, guanfacine) or repetitive transcranial magnetic stimulation manipulation provide a rational basis for therapy.

The meso-connectomes of mouse, marmoset, and macaque: network organization and the emergence of higher cognition.

The recent publications of the inter-areal connectomes for mouse, marmoset, and macaque cortex have allowed deeper comparisons across rodent vs. primate cortical organization. In general, these show that the mouse has very widespread, "all-to-all" inter-areal connectivity (i.e. a "highly dense" connectome in a graph theoretical framework), while primates have a more modular organization. In this review, we highlight the relevance of these differences to function, including the example of primary visual cortex (V1) which, in the mouse, is interconnected with all other areas, therefore including other primary sensory and frontal areas. We argue that this dense inter-areal connectivity benefits multimodal associations, at the cost of reduced functional segregation. Conversely, primates have expanded cortices with a modular connectivity structure, where V1 is almost exclusively interconnected with other visual cortices, themselves organized in relatively segregated streams, and hierarchically higher cortical areas such as prefrontal cortex provide top-down regulation for specifying precise information for working memory storage and manipulation. Increased complexity in cytoarchitecture, connectivity, dendritic spine density, and receptor expression additionally reveal a sharper hierarchical organization in primate cortex. Together, we argue that these primate specializations permit separable deconstruction and selective reconstruction of representations, which is essential to higher cognition.

Key Roles of CACNA1C/Cav1.2 and CALB1/Calbindin in Prefrontal Neurons Altered in Cognitive Disorders.

Importance: The risk of mental disorders is consistently associated with variants in CACNA1C (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. Objective: To examine the molecular mechanisms expressed in layer III pyramidal cells in primate dorsolateral prefrontal cortices. Design, Setting, and Participants: The 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 Measures: Outcome 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. Results: Layer III pyramidal cells in dorsolateral prefrontal cortex coexpress a constellation of calcium-related proteins, delineated by CALB1 (calbindin), and high levels of CACNA1C (Cav1.2), GRIN2B (NMDA receptor GluN2B), and KCNN3 (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 ß1-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 ß1-adrenoceptor antagonist protected working memory from stress. Conclusions and Relevance: The 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 in CACNA1C were 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.

Nanoscale imaging of pT217-tau in aged rhesus macaque entorhinal and dorsolateral prefrontal cortex: Evidence of interneuronal trafficking and early-stage neurodegeneration.

INTRODUCTION: Tau phosphorylated at threonine-217 (pT217-tau) is a novel fluid-based biomarker that predicts onset of Alzheimer's disease (AD) symptoms, but little is known about how pT217-tau arises in the brain, as soluble pT217-tau is dephosphorylated post mortem in humans. METHODS: We used multilabel immunofluorescence and immunoelectron microscopy to examine the subcellular localization of early-stage pT217-tau in entorhinal and prefrontal cortices of aged macaques with naturally occurring tau pathology and assayed pT217-tau levels in plasma. RESULTS: pT217-tau was aggregated on microtubules within dendrites exhibiting early signs of degeneration, including autophagic vacuoles. It was also seen trafficking between excitatory neurons within synapses on spines, where it was exposed to the extracellular space, and thus accessible to cerebrospinal fluid (CSF)/blood. Plasma pT217-tau levels increased across the age span and thus can serve as a biomarker in macaques. DISCUSSION: These data help to explain why pT217-tau predicts degeneration in AD and how it gains access to CSF and plasma to serve as a fluid biomarker.

Dynamic Network Connectivity: from monkeys to humans.

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.