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Attention-deficit/hyperactivity disorder (ADHD) is a common childhood-onset neuropsychiatric disorder characterized by cardinal features of inattention, locomotor hyperactivity, and poor impulse control. Research indicates that ADHD is associated with alterations in the higher cortical circuits that mediate attention and behavioral control. Given the prominent role of the prefrontal association cortex in regulating cognition and behavior through its extensive connections to sensory and motor cortices as well as subcortical structures, impairments in prefrontal function are believed to underlie many of the behavioral features of ADHD. Prefrontal cortex is sensitively modulated by numerous neurotransmitters including catecholamines, and changes in levels of dopamine-l and norepinephrine ([alpha]2A-adrenoceptor stimulation are associated with prominent effects on prefrontal function. Effective treatments for ADHD (including stimulants, atomoxetine, and guanfacine) influence catecholamine signaling in the prefrontal cortex and are believed to ameliorate ADHD symptoms via their effects on improved prefrontal cortical regulation of attention and impulse control. [ABSTRACT FROM AUTHOR]

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 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 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.

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 α 2A 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 α 2A adrenergic receptor agonist, guanfacine) or repetitive transcranial magnetic stimulation manipulation provide a rational basis for therapy., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

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., (© The Author(s) 2024. Published by Oxford University Press.)

The ability of monkeys and rats to carry out spatial working memory tasks has been shown to depend on the persistent firing of pyramidal cells in the prefrontal cortex (PFC), arising from recurrent excitatory connections on dendritic spines. These spines express hyperpolarization-activated cyclic nucleotide-gated (HCN) channels whose open state is increased by cAMP signaling, and which markedly alter PFC network connectivity and neuronal firing. In traditional neural circuits, activation of these non-selective cation channels leads to neuronal depolarization and increased firing rate. Paradoxically, cAMP activation of HCN channels in PFC pyramidal cells reduces working memory-related neuronal firing. This suggests that activation of HCN channels may hyperpolarize rather than depolarize these neurons. The current study tested the hypothesis that Na + influx through HCN channels activates Slack Na + -activated K + (K Na ) channels to hyperpolarize the membrane. We have found that HCN and Slack K Na channels co-immunoprecipitate in cortical extracts and that, by immunoelectron microscopy, they colocalize at postsynaptic spines of PFC pyramidal neurons. A specific blocker of HCN channels, ZD7288, reduces K Na current in pyramidal cells that express both HCN and Slack channels, but has no effect on K Na currents in an HEK cell line expressing Slack without HCN channels, indicating that blockade of HCN channels in neurons reduces K + current indirectly by lowering Na + influx. Activation of HCN channels by cAMP in a cell line expressing a Ca 2+ reporter results in elevation of cytoplasmic Ca 2+ , but the effect of cAMP is reversed if the HCN channels are co-expressed with Slack channels. Finally, we used a novel pharmacological blocker of Slack channels to show that inhibition of Slack in rat PFC improves working memory performance, an effect previously demonstrated for blockers of HCN channels. Our results suggest that the regulation of working memory by HCN channels in PFC pyramidal neurons is mediated by an HCN-Slack channel complex that links activation HCN channels to suppression of neuronal excitability., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Uncontrollable stress exposure impairs working memory and reduces the firing of dorsolateral prefrontal cortex (dlPFC) "Delay cells", involving high levels of norepinephrine and dopamine release. Previous work has focused on catecholamine actions on dlPFC pyramidal cells, but inhibitory interneurons may contribute as well. The current study combined immunohistochemistry and multi-scale microscopy with iontophoretic physiology and behavioral analyses to examine the effects of beta1-noradrenergic receptors (β1-ARs) on inhibitory neurons in layer III dlPFC. We found β1-AR robustly expressed on different classes of inhibitory neurons labeled by the calcium-binding proteins calbindin (CB), calretinin (CR), and parvalbumin (PV). Immunoelectron microscopy confirmed β1-AR expression on the plasma membrane of PV-expressing dendrites. PV interneurons can be identified as fast-spiking (FS) in physiological recordings, and thus were studied in macaques performing a working memory task. Iontophoresis of a β1-AR agonist had a mixed effect, increasing the firing of a subset and decreasing the firing of others, likely reflecting loss of firing of the entire microcircuit. This loss of overall firing likely contributes to impaired working memory during stress, as pretreatment with the selective β1-AR antagonist, nebivolol, prevented stress-induced working memory deficits. Thus, selective β1-AR antagonists may be helpful in treating stress-related disorders., Competing Interests: The authors have no conflicts of interest with this study., (© 2024 Published by Elsevier Inc.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Arnsten, Wang and D’Esposito.)

Alzheimer's disease cortical tau pathology initiates in the layer II cell clusters of entorhinal cortex, but it is not known why these specific neurons are so vulnerable. Aging macaques exhibit the same qualitative pattern of tau pathology as humans, including initial pathology in layer II entorhinal cortex clusters, and thus can inform etiological factors driving selective vulnerability. Macaque data have already shown that susceptible neurons in dorsolateral prefrontal cortex express a "signature of flexibility" near glutamate synapses on spines, where cAMP-PKA magnification of calcium signaling opens nearby potassium and hyperpolarization-activated cyclic nucleotide-gated channels to dynamically alter synapse strength. This process is regulated by PDE4A/D, mGluR3, and calbindin, to prevent toxic calcium actions; regulatory actions that are lost with age/inflammation, leading to tau phosphorylation. The current study examined whether a similar "signature of flexibility" expresses in layer II entorhinal cortex, investigating the localization of PDE4D, mGluR3, and HCN1 channels. Results showed a similar pattern to dorsolateral prefrontal cortex, with PDE4D and mGluR3 positioned to regulate internal calcium release near glutamate synapses, and HCN1 channels concentrated on spines. As layer II entorhinal cortex stellate cells do not express calbindin, even when young, they may be particularly vulnerable to magnified calcium actions and ensuing tau pathology., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Neuroinflammatory disorders preferentially impair the higher cognitive and executive functions of the prefrontal cortex (PFC). This includes such challenging disorders as delirium, perioperative neurocognitive disorder, and the sustained cognitive deficits from "long-COVID" or traumatic brain injury. There are no FDA-approved treatments for these symptoms; thus, understanding their etiology is important for generating therapeutic strategies. The current review describes the molecular rationale for why PFC circuits are especially vulnerable to inflammation, and how α2A-adrenoceptor (α2A-AR) actions throughout the nervous and immune systems can benefit the circuits in PFC needed for higher cognition. The layer III circuits in the dorsolateral PFC (dlPFC) that generate and sustain the mental representations needed for higher cognition have unusual neurotransmission and neuromodulation. They are wholly dependent on NMDAR neurotransmission, with little AMPAR contribution, and thus are especially vulnerable to kynurenic acid inflammatory signaling which blocks NMDAR. Layer III dlPFC spines also have unusual neuromodulation, with cAMP magnification of calcium signaling in spines, which opens nearby potassium channels to rapidly weaken connectivity and reduce neuronal firing. This process must be tightly regulated, e.g. by mGluR3 or α2A-AR on spines, to prevent loss of firing. However, the production of GCPII inflammatory signaling reduces mGluR3 actions and markedly diminishes dlPFC network firing. Both basic and clinical studies show that α2A-AR agonists such as guanfacine can restore dlPFC network firing and cognitive function, through direct actions in the dlPFC, but also by reducing the activity of stress-related circuits, e.g. in the locus coeruleus and amygdala, and by having anti-inflammatory actions in the immune system. This information is particularly timely, as guanfacine is currently the focus of large clinical trials for the treatment of delirium, and in open label studies for the treatment of cognitive deficits from long-COVID., (© 2023. The Author(s).)

Introduction: Current approaches for treating sporadic Alzheimer's disease (sAD) focus on removal of amyloid beta 1-42 (Aβ 1-42 ) or phosphorylated tau, but additional strategies are needed to reduce neuropathology at earlier stages prior to neuronal damage. Longstanding data show that calcium dysregulation is a key etiological factor in sAD, and the cortical neurons most vulnerable to tau pathology show magnified calcium signaling, for example in dorsolateral prefrontal cortex (dlPFC) and entorhinal cortex (ERC). In primate dlPFC and ERC, type 3 metabotropic glutamate receptors (mGluR3s) are predominately post-synaptic, on spines, where they regulate cAMP-calcium signaling, a process eroded by inflammatory glutamate carboxypeptidase II (GCPII) actions. The current study tested whether enhancing mGluR3 regulation of calcium via chronic inhibition of GCPII would reduce tau hyperphosphorylation in aged macaques with naturally-occurring tau pathology., Methods: Aged rhesus macaques were treated daily with the GCPII inhibitor, 2-MPPA (2-3-mercaptopropyl-penanedioic acid (2-MPPA)),Aged rhesus macaques were treated daily with the GCPII inhibitor, 2-MPPA (2-3-mercaptopropyl-penanedioic acid (2-MPPA))., Results: Aged macaques that received 2-MPPA had significantly lower pT217Tau levels in dlPFC and ERC, and had lowered plasma pT217Tau levels from baseline. pT217Tau levels correlated significantly with GCPII activity in dlPFC. Both 2-MPPA- and vehicle-treated monkeys showed cognitive improvement; 2-MPPA had no apparent side effects. Exploratory CSF analyses indicated reduced pS202Tau with 2-MPPA administration, confirmed in dlPFC samples., Discussion: These data provide proof-of-concept support that GCPII inhibition can reduce tau hyperphosphorylation in the primate cortices most vulnerable in sAD. GCPII inhibition may be particularly helpful in reducing the risk of sAD caused by inflammation. These data in nonhuman primates should encourage future research on this promising mechanism., Highlights: Inflammation is a key driver of sporadic Alzheimer's disease.GCPII inflammatory signaling in brain decreases mGluR3 regulation of calcium.Chronic inhibition of GCPII inflammatory signaling reduced pT217Tau in aged monkeys.GCPII inhibition is a novel strategy to help prevent tau pathology at early stages., Competing Interests: The authors have no financial conflicts of interest to disclose., (© 2023 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Patricia Goldman-Rakic (1937-2003), the co-founder of this journal, was a pioneering neuroscientist who made transformational discoveries about the prefrontal cortex and the neurobiological basis of working memory. Her research served as the foundation for cognitive neuroscience, and paved the path for women in science. Her multidisciplinary approach created a new paradigm, where the scientific question, rather than a single method, was paramount to the investigation. The current review provides a brief summary of her extraordinary life and scientific contributions., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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.

ARNSTEN, A.F.T., M.K.P. Joyce and A.C. Roberts. The Aversive Lens: Stress effects on the prefrontal-cingulate cortical pathways that regulate emotion. NEUROSCI BIOBEHAV REV XXX-XXX, 2022. The symptoms of major-depressive-disorder include psychic pain and anhedonia, i.e. seeing the world through an "aversive lens". The neurobiology underlying this shift in worldview is emerging. Here these data are reviewed, focusing on how activation of subgenual cingulate (BA25) induces an "aversive lens", and how higher prefrontal cortical (PFC) areas (BA46/10/32) provide top-down regulation of BA25 but are weakened by excessive dopamine and norepinephrine release during stress exposure, and dendritic spine loss with chronic stress exposure. These changes may generate an attractor state, which maintains the brain under the control of BA25, requiring medication or neuromodulatory treatments to return connectivity to a more flexible state. In line with this hypothesis, effective anti-depressant treatments reduce the activity of BA25 and restore top-down regulation by higher circuits, e.g. as seen with SSRI medications, ketamine, deep brain stimulation of BA25, or rTMS to strengthen dorsolateral PFC. This research has special relevance in an era of chronic stress caused by the COVID19 pandemic, political unrest and threat of climate change., Competing Interests: Conflict of interest None., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Synaptic loss is considered an early pathological event and major structural correlate of cognitive impairment in Alzheimer's disease (AD). We used principal component analysis (PCA) to identify regional patterns of covariance in synaptic density using [ 11 C]UCB-J PET and assessed the association between principal components (PC) subject scores with cognitive performance., Methods: [ 11 C]UCB-J binding was measured in 45 amyloid + participants with AD and 19 amyloid- cognitively normal participants aged 55-85. A validated neuropsychological battery assessed performance across five cognitive domains. PCA was applied to the pooled sample using distribution volume ratios (DVR) standardized (z-scored) by region from 42 bilateral regions of interest (ROI)., Results: Parallel analysis determined three significant PCs explaining 70.2% of the total variance. PC1 was characterized by positive loadings with similar contributions across the majority of ROIs. PC2 was characterized by positive and negative loadings with strongest contributions from subcortical and parietooccipital cortical regions, respectively, while PC3 was characterized by positive and negative loadings with strongest contributions from rostral and caudal cortical regions, respectively. Within the AD group, PC1 subject scores were positively correlated with performance across all cognitive domains (Pearson r = 0.24-0.40, P = 0.06-0.006), PC2 subject scores were inversely correlated with age (Pearson r = -0.45, P = 0.002) and PC3 subject scores were significantly correlated with CDR-sb (Pearson r = 0.46, P = 0.04). No significant correlations were observed between cognitive performance and PC subject scores in CN participants., Conclusions: This data-driven approach defined specific spatial patterns of synaptic density correlated with unique participant characteristics within the AD group. Our findings reinforce synaptic density as a robust biomarker of disease presence and severity in the early stages of AD., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: APM, REC, and CHvD report grants from National Institutes of Health for the conduct of the study. APM reports grants for clinical trials from Genentech, Eli Lilly, and Janssen Pharmaceuticals outside the submitted work. MKC reports research support from the Dana Foundation and Eli Lilly and clinical trials from Merck outside the submitted work. YH reports research grants from the UCB and Eli Lilly outside the submitted work. YH, NBN, and REC have a patent for a newer version of the tracer. REC is a consultant for Rodin Therapeutics and has received research funding from UCB. REC reports having received grants from AstraZeneca, Astellas, Eli Lilly, Pfizer, Taisho, and UCB, outside the submitted work. CHvD reports consulting fees from Kyowa Kirin, Roche, Merck, Eli Lilly, and Janssen and grants for clinical trials from Biogen, Novartis, Eli Lilly, Merck, Eisai, Janssen, Roche, Genentech, Toyama, and Biohaven, outside the submitted work. No other disclosures are reported. AHC has licensed technology to Elysium Health, Inc. and hasreceived consulting fees from FOXO Technologies, Inc., bothfor work unrelated to the present manuscript., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: For 30 years synapse loss has been referred to as the major pathological correlate of cognitive impairment in Alzheimer's disease (AD). However, this statement is based on remarkably few patients studied by autopsy or biopsy. With the recent advent of synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) imaging, we have begun to evaluate the consequences of synaptic alterations in vivo., Methods: We examined the relationship between synaptic density measured by [ 11 C]UCB-J PET and neuropsychological test performance in 45 participants with early AD., Results: Global synaptic density showed a significant positive association with global cognition and performance on five individual cognitive domains in participants with early AD. Synaptic density was a stronger predictor of cognitive performance than gray matter volume., Conclusion: These results confirm neuropathologic studies demonstrating a significant association between synaptic density and cognitive performance, and suggest that this correlation extends to the early stages of AD., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Glutamate carboxypeptidase-II (GCPII) expression in brain is increased by inflammation, e.g. by COVID19 infection, where it reduces NAAG stimulation of metabotropic glutamate receptor type 3 (mGluR3). GCPII-mGluR3 signaling is increasingly linked to higher cognition, as genetic alterations that weaken mGluR3 or increase GCPII signaling are associated with impaired cognition in humans. Recent evidence from macaque dorsolateral prefrontal cortex (dlPFC) shows that mGluR3 are expressed on dendritic spines, where they regulate cAMP-PKA opening of potassium (K + ) channels to enhance neuronal firing during working memory. However, little is known about GCPII expression and function in the primate dlPFC, despite its relevance to inflammatory disorders. The present study used multiple label immunofluorescence and immunoelectron microscopy to localize GCPII in aging macaque dlPFC, and examined the effects of GCPII inhibition on dlPFC neuronal physiology and working memory function. GCPII was observed in astrocytes as expected, but also on neurons, including extensive expression in dendritic spines. Recordings in dlPFC from aged monkeys performing a working memory task found that iontophoresis of the GCPII inhibitors 2-MPPA or 2-PMPA markedly increased working memory-related neuronal firing and spatial tuning, enhancing neural representations. These beneficial effects were reversed by an mGluR2/3 antagonist, or by a cAMP-PKA activator, consistent with mGluR3 inhibition of cAMP-PKA-K + channel signaling. Systemic administration of the brain penetrant inhibitor, 2-MPPA, significantly improved working memory performance without apparent side effects, with largest effects in the oldest monkeys. Taken together, these data endorse GCPII inhibition as a potential strategy for treating cognitive disorders associated with aging and/or neuroinflammation., (© 2022. The Author(s).)

Extensive preclinical and emerging clinical evidence point to an involvement of the kappa opioid receptor (KOR) in brain networks that promotes neurobehavioral stability. KOR expression in mesolimbic and mesocortical pathways has been the basis for characterizing the role of this receptor system in regulating motivation and emotion; however, the involvement of the KOR system in higher-order executive processes such as working memory (WM) is not well-understood. WM is readily impaired with uncontrollable stress exposure and is dysregulated in many neurobehavioral disorders. To empirically evaluate the role of the KOR system on WM performance, we administered a selective KOR antagonist, NMRA-140 (0, 0.1, 0.3, 1.0 mg/kg, intramuscular) to monkeys under both stress and non-stress conditions. In this study, NMRA-140 was co-administered with FG7142, a benzodiazepine inverse agonist, known to produce a mild stress response and to impair WM function in monkeys. NMRA-140 protected WM performance from the detrimental effects of FG7142-induced stress and exhibited no significant effect under non-stress conditions. Collectively, these data highlight the functional influence of the KOR system in mediating stress-induced dysfunction of executive processes and suggest that modulating KOR activity could offer therapeutic benefit in stress-related neurobehavioral disorders., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: T.L. Wallace is an employee of Neumora Therapeutics, Inc. (which acquired BlackThorn Therapeutics, Inc.) and has ownership interest (stock, stock options, royalty, receipt of intellectual property rights/patent holder, excluding diversified mutual funds) in Neumora Therapeutics, Inc.; W.J. Martin, a former employee of BlackThorn Therapeutics, Inc., holds an ownership interest (stock) in Neumora Therapeutics, Inc. as a result of the acquisition of BlackThorn Therapeutics, Inc. by Neumora Therapeutics, Inc. in November 2020.; A.F.T. Arnsten had a Contracted Research/Research Grant with BlackThorn Therapeutics. A.F.T.A and Yale receive royalties from the USA sales of Intuniv (non-generic) from Shire/Takeda Pharma., (© 2022 The Authors.)

Schizophrenia is associated with reduced numbers of spines and dendrites from layer III of the dorsolateral prefrontal cortex (dlPFC), the layer that houses the recurrent excitatory microcircuits that subserve working memory and abstract thought. Why are these synapses so vulnerable, while synapses in deeper or more superficial layers are little affected? This review describes the special molecular properties that govern layer III neurotransmission and neuromodulation in the primate dlPFC and how they may render these circuits particularly vulnerable to genetic and environmental insults. These properties include a reliance on NMDA receptor rather than AMPA receptor neurotransmission; cAMP (cyclic adenosine monophosphate) magnification of calcium signaling near the glutamatergic synapse of dendritic spines; and potassium channels opened by cAMP/PKA (protein kinase A) signaling that dynamically alter network strength, with built-in mechanisms to take dlPFC "offline" during stress. A variety of genetic and/or environmental insults can lead to the same phenotype of weakened layer III connectivity, in which mechanisms that normally strengthen connectivity are impaired and those that normally weaken connectivity are intensified. Inflammatory mechanisms, such as increased kynurenic acid and glutamate carboxypeptidase II expression, are especially detrimental to layer III dlPFC neurotransmission and modulation, mimicking genetic insults. The combination of genetic and inflammatory insults may cross the threshold into pathology., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Metabotropic glutamate receptors type 3 (mGlu3, encoded by GRM3 ) are increasingly related to cognitive functioning, including the working memory operations of the prefrontal cortex (PFC). In rhesus monkeys, mGlu3 are most commonly expressed on glia (36%), but are also very prominent on layer III dendritic spines (23%) in the dorsolateral PFC (dlPFC) where they enhance working memory-related neuronal firing. In contrast, mGlu2 are predominately presynaptic in layer III of macaque dlPFC, indicating a pre- vs. post-synaptic dissociation by receptor subtype. The current study examined the cellular and subcellular localizations of mGlu3 in the rat prelimbic medial PFC (PL mPFC), a region needed for spatial working memory performance in rodents. Multiple label immunofluorescence demonstrated mGlu3 expression in neurons and astrocytes, with rare labeling in microglia. Immunoelectron microscopy of layers III and V found that the predominant location for mGlu3 was on axons (layer III: 35.9%; layer V: 44.1%), with labeling especially prominent within the intervaricose segments distant from axon terminals. mGlu3 were also found on glia (likely astrocytes), throughout the glial membrane (layer III: 28.2%; layer V: 29.5%). Importantly, mGlu3 could be seen on dendritic spines, especially in layer III (layer III: 15.6%; layer V: 8.2%), with minor labeling on dendrites. These data show that there are some similarities between mGlu3 expression in rat PL mPFC and macaque dlPFC, but the spine expression enriches and differentiates in the more recently evolved primate dlPFC., Competing Interests: Yale University and AA received royalties from Shire/Takeda from the USA sales of Intuniv (extended release guanfacine). They do not receive royalties from international sales, nor from sales of generic Intuniv. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Woo, Datta and Arnsten.)

Sites of early neuropathologic change provide important clues regarding the initial clinical features of Alzheimer's disease (AD). We have shown significant reductions in hippocampal synaptic density in participants with AD, consistent with the early degeneration of entorhinal cortical (ERC) cells that project to hippocampus via the perforant path. In this study, [ 11 C]UCB-J binding to synaptic vesicle glycoprotein 2A (SV2A) and [ 18 F]flortaucipir binding to tau were measured via PET in 10 participants with AD (5 mild cognitive impairment, 5 mild dementia) and 10 cognitively normal participants. In the overall sample, ERC tau was inversely associated with hippocampal synaptic density (r = -0.59, p = 0.009). After correction for partial volume effects, the association of ERC tau with hippocampal synaptic density was stronger in the overall sample (r = -0.61, p = 0.007) and in the AD group where the effect size was large, but not statistically significant (r = -0.58, p = 0.06). This inverse association of ERC tau and hippocampal synaptic density may reflect synaptic failure due to tau pathology in ERC neurons projecting to the hippocampus., (Copyright © 2021. Published by Elsevier Inc.)

The primate prefrontal cortex (PFC) subserves our highest order cognitive operations, and yet is tremendously dependent on a precise neurochemical environment for proper functioning. Depletion of noradrenaline and dopamine, or of acetylcholine from the dorsolateral PFC (dlPFC), is as devastating as removing the cortex itself, and serotonergic influences are also critical to proper functioning of the orbital and medial PFC. Most neuromodulators have a narrow inverted U dose response, which coordinates arousal state with cognitive state, and contributes to cognitive deficits with fatigue or uncontrollable stress. Studies in monkeys have revealed the molecular signaling mechanisms that govern the generation and modulation of mental representations by the dlPFC, allowing dynamic regulation of network strength, a process that requires tight regulation to prevent toxic actions, e.g., as occurs with advanced age. Brain imaging studies in humans have observed drug and genotype influences on a range of cognitive tasks and on PFC circuit functional connectivity, e.g., showing that catecholamines stabilize representations in a baseline-dependent manner. Research in monkeys has already led to new treatments for cognitive disorders in humans, encouraging future research in this important field., (© 2021. The Author(s).)

Age is the most significant risk factor for Alzheimer's disease (AD), and understanding its role in specific aspects of AD pathology will be critical for therapeutic development. Neurofibrillary tangles composed of hyperphosphorylated tau are a quintessential hallmark of AD. To study age-related changes in tau phosphorylation, we developed a simple, antibody-free approach for single shot analysis of tau phosphorylation across the entire protein by liquid-chromatography tandem mass spectrometry. This methodology is species independent; thus, while initially developed in a rodent model, we utilized this technique to analyze 36 phosphorylation sites on rhesus monkey tau from the prefrontal cortex (PFC), a region vulnerable to AD-linked degeneration. Data are available via ProteomeXchange with identifier PXD027971. We identified novel, age-related changes in tau phosphorylation in the rhesus monkey PFC and analyzed patterns of phosphorylation change across domains of the protein. We confirmed a significant increase and positive correlation with age of phosphorylated serine 235 tau and phosphorylated serine 396 tau levels in an expanded cohort of 14 monkeys. Histology showed robust labeling for tau phosphorylated at these sites in vulnerable layer III pyramidal cells in the PFC. The results presented in this study suggest an important role of the natural aging process in tau phosphorylation in rhesus monkey., Competing Interests: AA and Yale University receive royalties from Shire/Takeda from the United States sales of Intuniv™. They do not receive royalties from international sales or generic Intuniv™. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Leslie, Kanyo, Datta, Wilson, Zeiss, Duque, Lam, Arnsten and Nairn.)

Glutamate carboxypeptidase II (GCPII) expression in brain is increased by inflammation, and reduces NAAG (N-acetyl aspartyl glutamate) stimulation of mGluR3 signaling. Genetic insults in this signaling cascade are increasingly linked to cognitive disorders in humans, where increased GCPII and or decreased NAAG-mGluR3 are associated with impaired prefrontal cortical (PFC) activation and cognitive impairment. As aging is associated with increased inflammation and PFC cognitive deficits, the current study examined GCPII and mGluR3 expression in the aging rat medial PFC, and tested whether GCPII inhibition with 2-(3-mercaptopropyl) pentanedioic acid (2-MPPA) would improve working memory performance. We found that GCPII protein was expressed on astrocytes and some microglia as expected from previous studies, but was also prominently expressed on neurons, and showed increased levels with advancing age. Systemic administration of the GCPII inhibitor, 2-MPPA, improved working memory performance in young and aged rats, and also improved performance after local infusion into the medial PFC. As GCPII inhibitors are well-tolerated, they may provide an important new direction for treatment of cognitive disorders associated with aging and/or inflammation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Datta, Leslie, Woo, Amancharla, Elmansy, Lepe, Mecca, Slusher, Nairn and Arnsten.)

Tau pathology in Alzheimer's disease (AD) preferentially afflicts the limbic and recently enlarged association cortices, causing a progression of mnemonic and cognitive deficits. Although genetic mouse models have helped reveal mechanisms underlying the rare, autosomal-dominant forms of AD, the etiology of the more common, sporadic form of AD remains unknown, and is challenging to study in mice due to their limited association cortex and lifespan. It is also difficult to study in human brains, as early-stage tau phosphorylation can degrade postmortem. In contrast, rhesus monkeys have extensive association cortices, are long-lived, and can undergo perfusion fixation to capture early-stage tau phosphorylation in situ. Most importantly, rhesus monkeys naturally develop amyloid plaques, neurofibrillary tangles comprised of hyperphosphorylated tau, synaptic loss, and cognitive deficits with advancing age, and thus can be used to identify the early molecular events that initiate and propel neuropathology in the aging association cortices. Studies to date suggest that the particular molecular signaling events needed for higher cognition-for example, high levels of calcium to maintain persistent neuronal firing- lead to tau phosphorylation and inflammation when dysregulated with advancing age. The expression of NMDAR-NR2B (GluN2B)-the subunit that fluxes high levels of calcium-increases over the cortical hierarchy and with the expansion of association cortex in primate evolution, consistent with patterns of tau pathology. In the rhesus monkey dorsolateral prefrontal cortex, spines contain NMDAR-NR2B and the molecular machinery to magnify internal calcium release near the synapse, as well as phosphodiesterases, mGluR3, and calbindin to regulate calcium signaling. Loss of regulation with inflammation and/or aging appears to be a key factor in initiating tau pathology. The vast expansion in the numbers of these synapses over primate evolution is consistent with the degree of tau pathology seen across species: marmoset < rhesus monkey < chimpanzee < human, culminating in the vast neurodegeneration seen in humans with AD., (© 2021 The Authors. American Journal of Primatology Published by Wiley Periodicals LLC.)

Chronic exposure to uncontrollable stress causes loss of spines and dendrites in the prefrontal cortex (PFC), a recently evolved brain region that provides top-down regulation of thought, action, and emotion. PFC neurons generate top-down goals through recurrent excitatory connections on spines. This persistent firing is the foundation for higher cognition, including working memory, and abstract thought. However, exposure to acute uncontrollable stress drives high levels of catecholamine release in the PFC, which activates feedforward calcium-cAMP signaling pathways to open nearby potassium channels, rapidly weakening synaptic connectivity to reduce persistent firing. Chronic stress exposures can further exacerbate these signaling events leading to loss of spines and resulting in marked cognitive impairment. In this review, we discuss how stress signaling mechanisms can lead to spine loss, including changes to BDNF-mTORC1 signaling, calcium homeostasis, actin dynamics, and mitochondrial actions that engage glial removal of spines through inflammatory signaling. Stress signaling events may be amplified in PFC spines due to cAMP magnification of internal calcium release. As PFC dendritic spine loss is a feature of many cognitive disorders, understanding how stress affects the structure and function of the PFC will help to inform strategies for treatment and prevention., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Yale University and AFTA receive royalties from Shire/Takeda from the USA sales of extended release guanfacine (Intuniv). They do not receive royalties from international nor generic sales of Intuniv., (© The Author(s) 2021.)

Neurons in the association cortices are particularly vulnerable in cognitive disorders such as schizophrenia and Alzheimer's disease, while those in primary visual cortex remain relatively resilient. This review proposes that the special molecular mechanisms needed for higher cognitive operations confer vulnerability to dysfunction, atrophy, and neurodegeneration when regulation is lost due to genetic and/or environmental insults. Accumulating data suggest that higher cortical circuits rely on magnified levels of calcium (from NMDAR, calcium channels, and/or internal release from the smooth endoplasmic reticulum) near the postsynaptic density to promote the persistent firing needed to maintain, manipulate, and store information without "bottom-up" sensory stimulation. For example, dendritic spines in the primate dorsolateral prefrontal cortex (dlPFC) express the molecular machinery for feedforward, cAMP-PKA-calcium signaling. PKA can drive internal calcium release and promote calcium flow through NMDAR and calcium channels, while in turn, calcium activates adenylyl cyclases to produce more cAMP-PKA signaling. Excessive levels of cAMP-calcium signaling can have a number of detrimental effects: for example, opening nearby K + channels to weaken synaptic efficacy and reduce neuronal firing, and over a longer timeframe, driving calcium overload of mitochondria to induce inflammation and dendritic atrophy. Thus, calcium-cAMP signaling must be tightly regulated, e.g., by agents that catabolize cAMP or inhibit its production (PDE4, mGluR3), and by proteins that bind calcium in the cytosol (calbindin). Many genetic or inflammatory insults early in life weaken the regulation of calcium-cAMP signaling and are associated with increased risk of schizophrenia (e.g., GRM3). Age-related loss of regulatory proteins which result in elevated calcium-cAMP signaling over a long lifespan can additionally drive tau phosphorylation, amyloid pathology, and neurodegeneration, especially when protective calcium binding proteins are lost from the cytosol. Thus, the "genie" we need for our remarkable cognitive abilities may make us vulnerable to cognitive disorders when we lose essential regulation., (© 2020. The Author(s).)

The COVID-19 pandemic is an unanticipated and uncontrollable chronic stressor that is detrimental to the mental and behavioral health of children and families, particularly those from disadvantaged and marginalized backgrounds. Chronic stress impairs a myriad of prefrontal cortical functions, important for coping with the COVID-19 pandemic, and has consequences on dyadic parent-child functioning. Informed by neuroscience and clinical evidence, sensitive parenting is a vital avenue of intervention that buffers against the toxic effects of COVID-19 on parent-child mental health. In the context of the COVID-19 pandemic, we first discuss the neurobiological, psychological, and behavioral mechanisms behind exacerbated mental health risks in families. We then highlight the role of sensitive parenting as a buffer against stress-related mental health problems, and conclude with recommendations for systemic-, family-, and individual-interventions to most effectively address stress-related mental health problems and their impact on children and families during the COVID-19 pandemic. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Introduction: The etiology of sporadic Alzheimer's disease (AD) requires non-genetically modified animal models., Methods: The relationship of tau phosphorylation to calcium-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) dysregulation was analyzed in aging rhesus macaque dorsolateral prefrontal cortex (dlPFC) and rat primary cortical neurons using biochemistry and immuno-electron microscopy. The influence of calcium leak from ryanodine receptors (RyRs) on neuronal firing and cognitive performance was examined in aged macaques., Results: Aged monkeys naturally develop hyperphosphorylated tau, including AD biomarkers (AT8 (pS202/pT205) and pT217) and early tau pathology markers (pS214 and pS356) that correlated with evidence of increased calcium leak (pS2808-RyR2). Calcium also regulated early tau phosphorylation in vitro. Age-related reductions in the calcium-binding protein, calbindin, and in phosphodiesterase PDE4D were seen within dlPFC pyramidal cell dendrites. Blocking RyRs with S107 improved neuronal firing and cognitive performance in aged macaques., Discussion: Dysregulated calcium signaling confers risk for tau pathology and provides a potential therapeutic target., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The dorsolateral prefrontal cortex (dlPFC) generates the mental representations that are the foundation of abstract thought, and provides top-down regulation of emotion through projections to the medial PFC and cingulate cortices. Physiological recordings from dlPFC Delay cells have shown that the generation of mental representations during working memory relies on NMDAR neurotransmission, with surprisingly little contribution from AMPAR. Systemic administration of low "antidepressant" doses of the NMDAR antagonist, ketamine, erodes these representations and reduces dlPFC Delay cell firing. In contrast to the dlPFC, V1 neuronal firing to visual stimuli depends on AMPAR, with much less contribution from NMDAR. Similarly, neurons in the dlPFC that respond to sensory events (cue cells, response feedback cells) rely on AMPAR, and systemic ketamine increases their firing. Insults to NMDAR transmission, and the impaired ability for dlPFC to generate mental representations, may contribute to cognitive deficits in schizophrenia, e.g., from genetic insults that weaken NMDAR transmission, or from blockade of NMDAR by kynurenic acid. Elevated levels of kynurenic acid in dlPFC may also contribute to cognitive deficits in other disorders with pronounced neuroinflammation (e.g., Alzheimer's disease), or peripheral infections where kynurenine can enter brain (e.g., delirium from sepsis, "brain fog" in COVID19). Much less is known about NMDAR actions in the primate cingulate cortices. However, NMDAR neurotransmission appears to process the affective and visceral responses to pain and other aversive experiences mediated by the cingulate cortices, which may contribute to sustained alterations in mood state. We hypothesize that the very rapid, antidepressant effects of intranasal ketamine may involve the disruption of NMDAR-generated aversive mood states by the anterior and subgenual cingulate cortices, providing a "foot in the door" to allow the subsequent return of top-down regulation by higher PFC areas. Thus, the detrimental vs. therapeutic effects of NMDAR blockade may be circuit dependent., Competing Interests: AA and Yale University receive royalties from Shire/Takeda from the USA sales of Intuniv. They do not receive royalties from generic or nonUSA sales. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yang, Seo, Wang and Arnsten.)

Physician burnout and other forms of occupational distress are a significant problem in modern medicine, especially during the coronavirus disease pandemic, yet few doctors are familiar with the neurobiology that contributes to these problems. Burnout has been linked to changes that reduce a physician's sense of control over their own practice, undermine connections with patients and colleagues, interfere with work-life integration, and result in uncontrolled stress. Brain research has revealed that uncontrollable stress, but not controllable stress, impairs the functioning of the prefrontal cortex, a recently evolved brain region that provides top-down regulation over thought, action, and emotion. The prefrontal cortex governs many cognitive operations essential to physicians, including abstract reasoning, higher-order decision making, insight, and the ability to persevere through challenges. However, the prefrontal cortex is remarkably reliant on arousal state and is impaired under conditions of fatigue and/or uncontrollable stress when there are inadequate or excessive levels of the arousal modulators (eg, norepinephrine, dopamine, acetylcholine). With chronic stress exposure, prefrontal gray matter connections are lost, but they can be restored by stress relief. Reduced prefrontal cortex self-regulation may explain several challenges associated with burnout in physicians, including reduced motivation, unprofessional behavior, and suboptimal communication with patients. Understanding this neurobiology may help physicians have a more informed perspective to help relieve or prevent symptoms of burnout and may help administrative leaders to optimize the work environment to create more effective organizations. Efforts to restore a sense of control to physicians may be particularly helpful., (Copyright © 2021 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Background: Attempts to associate amyloid-β (Aβ) pathogenesis with synaptic loss in Alzheimer's disease (AD) have thus far been limited to small numbers of postmortem studies. Aβ plaque burden is not well-correlated with indices of clinical severity or neurodegeneration-at least in the dementia stage-as deposition of Aβ reaches a ceiling. In this study, we examined in vivo the association between fibrillar Aβ deposition and synaptic density in early AD using positron emission tomography (PET). We hypothesized that global Aβ deposition would be more strongly inversely associated with hippocampal synaptic density in participants with amnestic mild cognitive impairment (aMCI; a stage of continued Aβ accumulation) compared to those with dementia (a stage of relative Aβ plateau)., Methods: We measured SV2A binding ([ 11 C]UCB-J) and Aβ deposition ([ 11 C]PiB) in 14 participants with aMCI due to AD and 24 participants with mild AD dementia. Distribution volume ratios (DVR) with a cerebellar reference region were calculated for both tracers to investigate the association between global Aβ deposition and SV2A binding in hippocampus. Exploratory analyses examined correlations between both global and regional Aβ deposition and SV2A binding across a broad range of brain regions using both ROI- and surface-based approaches., Results: We observed a significant inverse association between global Aβ deposition and hippocampal SV2A binding in participants with aMCI (r = - 0.55, P = 0.04), but not mild dementia (r = 0.05, P = 0.82; difference statistically significant by Fisher z = - 1.80, P = 0.04). Exploratory analyses across other ROIs and whole brain analyses demonstrated no broad or consistent associations between global Aβ deposition and regional SV2A binding in either diagnostic group. ROI-based analyses of the association between regional Aβ deposition and SV2A binding also revealed no consistent pattern but suggested a "paradoxical" positive association between local Aβ deposition and SV2A binding in the hippocampus., Conclusions: Our findings lend support to a model in which fibrillar Aβ is still accumulating in the early stages of clinical disease but approaching a relative plateau, a point at which Aβ may uncouple from neurodegenerative processes including synaptic loss. Future research should investigate the relationship between Aβ deposition and synaptic loss in larger cohorts beginning preclinically and followed longitudinally in conjunction with other biomarkers.

The etiology of the common, sporadic form of Alzheimer's disease (sAD) is unknown. We hypothesize that tau pathology within select projection neurons with susceptible microenvironments can initiate sAD. This postulate rests on extensive data demonstrating that in human brains tau pathology appears about a decade before the formation of Aβ plaques (Aβps), especially targeting glutamate projection neurons in the association cortex. Data from aging rhesus monkeys show abnormal tau phosphorylation within vulnerable neurons, associated with calcium dysregulation. Abnormally phosphorylated tau (pTau) on microtubules traps APP-containing endosomes, which can increase Aβ production. As Aβ oligomers increase abnormal phosphorylation of tau, this would drive vicious cycles leading to sAD pathology over a long lifespan, with genetic and environmental factors that may accelerate pathological events. This hypothesis could be testable in the aged monkey association cortex that naturally expresses characteristics capable of promoting and sustaining abnormal tau phosphorylation and Aβ production., (© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Rationale: Metabotropic glutamate type 5 receptor (mGluR5) antagonists are under development for treating cognitive disorders such as Fragile X syndrome and Alzheimer's disease, largely based on success in mouse models, where post-synaptic mGluR5 stimulation weakens synaptic functions in hippocampus. However, human trials of mGluR5 antagonists have yet to be successful. This may be due in part to the differing effects of mGluR5 in hippocampus vs. prefrontal cortex, as mGluR5 are primarily post-synaptic in rodent hippocampus, but are both pre- and post-synaptic in the dorsolateral prefrontal cortical (dlPFC) circuits known to subserve working memory., Objectives and Methods: The current study examined the effects of the selective mGluR5 negative allosteric modulator, MTEP (3-((2-Methyl-1,3-thiazol-4-yl)ethynyl)pyridine hydrochloride), on neuronal firing and working memory performance in aging rhesus monkeys with naturally occurring impairments in neuronal firing and cognitive performance., Results: We found that iontophoresis of MTEP directly onto dlPFC "Delay cells" had an inverted U dose-response, where low doses tended to enhance task-related firing, but higher doses suppressed neuronal firing. Similar effects were seen on cognitive performance following systemic MTEP administration (0.0001-0.1 mg/kg), with MTEP producing erratic dose-response curves. In the subset of monkeys (50%) that showed replicable improvement with MTEP, co-administration with the mGluR5 PAM, CDPPB (3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide), blocked MTEP beneficial effects, consistent with mGluR5 actions., Conclusions: The mixed effects of MTEP on cognitive performance may arise from opposing actions at pre- vs. post-synaptic mGluR5 in dlPFC. These data from monkeys suggest that future clinical trials should include low doses, and identification of potential subgroup responders.

The public health burden of Alzheimer's disease (AD) is related not only to cognitive symptoms, but also to neuropsychiatric symptoms, including apathy. Apathy is defined as a quantitative reduction of goal-directed activity in comparison to a previous level of functioning and affects 30%-70% of persons with AD. Previous attempts to treat apathy in AD-both nonpharmacologically and pharmacologically-have been wanting. Catecholaminergic treatment with methylphenidate has shown encouraging results in initial trials of apathy in AD. Understanding the neuronal circuits underlying motivated behavior and their reliance on catecholamine actions helps provide a rationale for methylphenidate actions in the treatment of apathy in patients with AD. Anatomical, physiological, and behavioral studies have identified parallel, cortical-basal ganglia circuits that govern action, cognition, and emotion and play key roles in motivated behavior. Understanding the distinct contributions to motivated behavior of subregions of the prefrontal cortex-dorsolateral, orbital-ventromedial, and dorsomedial-helps to explain why degeneration of these areas in AD results in apathetic behaviors. We propose that the degeneration of the prefrontal cortex in AD produces symptoms of apathy. We further propose that methylphenidate treatment may ameliorate those symptoms by boosting norepinephrine and dopamine actions in prefrontal-striatal-thalamocortical circuits., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The selective norepinephrine (NE) α2A-adrenoceptor (α2A-AR) agonist, guanfacine (Intuniv™), is FDA-approved for treating Attention Deficit Hyperactivity Disorder (ADHD) based on research in animals, a translational success story. Guanfacine is also widely used off-label in additional mental disorders that involve impaired functioning of the prefrontal cortex (PFC), including stress-related disorders such as substance abuse, schizotypic cognitive deficits, and traumatic brain injury. The PFC subserves high order cognitive and executive functions including working memory, abstract reasoning, insight and judgment, and top-down control of attention, action and emotion. These abilities arise from PFC microcircuits with extensive recurrent excitation through NMDAR synapses. There is powerful modulation of these synapses, where cAMP-PKA opening of nearby potassium (K + ) channels can rapidly and dynamically alter synaptic strength to coordinate arousal state with cognitive state, e.g. to take PFC "offline" during uncontrollable stress. A variety of evidence shows that guanfacine acts within the PFC via post-synaptic α2A-AR on dendritic spines to inhibit cAMP-PKA-K + channel signaling, thus strengthening network connectivity, enhancing PFC neuronal firing, and improving PFC cognitive functions. Although guanfacine's beneficial effects are present in rodent, they are especially evident in primates, where the PFC greatly expands and differentiates. In addition to therapeutic actions in PFC, stress-related disorders may also benefit from additional α2-AR actions, such as weakening plasticity in the amygdala, reducing NE release, and anti-inflammatory actions by deactivating microglia. Altogether, these NE α2-AR actions optimize top-down control by PFC networks, which may explain guanfacine's benefits in a variety of mental disorders., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

cAMP signaling has powerful, negative effects on cognitive functions of the primate dorsolateral prefrontal cortex (dlPFC), opening potassium channels to reduce firing and impair working memory, and increasing tau phosphorylation in aging neurons. This contrasts with cAMP actions in classic circuits, where it enhances plasticity and transmitter release. PDE4 isozymes regulate cAMP actions, and thus have been a focus of research and drug discovery. Previous work has focused on the localization of PDE4A and PDE4B in dlPFC, but PDE4D is also of great interest, as it is the predominant PDE4 isoform in primate association cortex, and PDE4D expression decreases with aging in human dlPFC. Here we used laser-capture microdissection transcriptomics and found that PDE4D message is enriched in pyramidal cells compared to GABAergic PV-interneurons in layer III of the human dlPFC. A parallel study in rhesus macaques using high-spatial resolution immunoelectron microscopy revealed the ultrastructural locations of PDE4D in primate dlPFC with clarity not possible in human post-mortem tissue. PDE4D was especially prominent in dendrites associated with microtubules, mitochondria, and likely smooth endoplasmic reticulum (SER). There was substantial postsynaptic labeling in dendritic spines, associated with the SER spine-apparatus near glutamatergic-like axospinous synapses, but sparse labeling in axon terminals. We also observed dense PDE4D labeling perisynaptically in astroglial leaflets ensheathing glutamatergic connections. These data suggest that PDE4D is strategically positioned to regulate cAMP signaling in dlPFC glutamatergic synapses and circuits, especially in postsynaptic compartments where it is localized to influence cAMP actions on intracellular trafficking, mitochondrial physiology, and internal calcium release., (Copyright © 2020 Datta, Enwright, Arion, Paspalas, Morozov, Lewis and Arnsten.)

Age is the largest risk factor for Alzheimer's disease (AD) and contributes to cognitive impairment in otherwise healthy individuals. Thus, it is critical that we better understand the risk aging presents to vulnerable regions of the brain and carefully design therapeutics to address those effects. In this study we examined age-related changes in cAMP-regulatory protein, phosphodiesterase 4D (PDE4D). Inhibition of PDE4D is currently under investigation as a therapeutic target for AD based on memory-enhancing effects in rodent hippocampus. Therefore, it is important to understand the role of PDE4D in brain regions particularly vulnerable to disease such as the frontal association cortex (FC), where cAMP signaling can impair working memory via opening of potassium channels. We found that PDE4D protein level was decreased in the FC of both moderately and extremely aged rats, and that PDE4D level was correlated with performance on a FC-dependent working memory task. In extremely aged rats, PDE4D was also inversely correlated with levels of phosphorylated tau at serine 214 (S214), a site phosphorylated by protein kinase A. In vitro studies of the PDE4D inhibitor, GEBR-7b, further illustrated that inhibition of PDE4D activity enhanced phosphorylation of tau. pS214-tau phosphorylation is associated with early AD tau pathology, promotes tau dissociation from microtubules and primes subsequent tau hyperphosphorylation at other critical AD-related sites. Age-related loss of PDE4D may thus contribute to the specific vulnerability of the FC to degeneration in AD, and play a critical role in normal cAMP regulation, cautioning against the use of pan-PDE4D inhibitors as therapeutics., (Copyright © 2020 Leslie, Datta, Christensen, van Dyck, Arnsten and Nairn.)

Introduction: Synaptic loss is a robust and consistent pathology in Alzheimer's disease (AD) and the major structural correlate of cognitive impairment. Positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) has emerged as a promising biomarker of synaptic density., Methods: We measured SV2A binding in 34 participants with early AD and 19 cognitively normal (CN) participants using [ 11 C]UCB-J PET and a cerebellar reference region for calculation of the distribution volume ratio., Results: We observed widespread reductions of SV2A binding in medial temporal and neocortical brain regions in early AD compared to CN participants. These reductions were largely maintained after correction for volume loss and were more extensive than decreases in gray matter volume., Conclusion: We were able to measure widespread synaptic loss due to AD using [ 11 C]UCB-J PET. Future studies will continue to evaluate the utility of SV2A PET for tracking AD progression and for monitoring potential therapies., (© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Working memory relies on the dorsolateral prefrontal cortex (dlPFC), where microcircuits of pyramidal neurons enable persistent firing in the absence of sensory input, maintaining information through recurrent excitation. This activity relies on acetylcholine, although the molecular mechanisms for this dependence are not thoroughly understood. This study investigated the role of muscarinic M1 receptors (M1Rs) in the dlPFC using iontophoresis coupled with single-unit recordings from aging monkeys with naturally occurring cholinergic depletion. We found that M1R stimulation produced an inverted-U dose response on cell firing and behavioral performance when given systemically to aged monkeys. Immunoelectron microscopy localized KCNQ isoforms (Kv7.2, Kv7.3, and Kv7.5) on layer III dendrites and spines, similar to M1Rs. Iontophoretic manipulation of KCNQ channels altered cell firing and reversed the effects of M1R compounds, suggesting that KCNQ channels are one mechanism for M1R actions in the dlPFC. These results indicate that M1Rs may be an appropriate target to treat cognitive disorders with cholinergic alterations., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Cognitive impairment in schizophrenia, aging, and Alzheimer's disease is associated with spine and synapse loss from the dorsolateral prefrontal cortex (dlPFC) layer III. Complement cascade signaling is critical in driving spine loss and disease pathogenesis. Complement signaling is initiated by C1q, which tags synapses for elimination. C1q is thought to be expressed predominately by microglia, but its expression in primate dlPFC has never been examined. The current study assayed C1q levels in aging primate dlPFC and rat medial PFC (mPFC) and used immunoelectron microscopy (immunoEM), immunoblotting, and co-immunoprecipitation (co-IP) to reveal the precise anatomical distribution and interactions of C1q., Methods: Age-related changes in C1q levels in rhesus macaque dlPFC and rat mPFC were examined using immunoblotting. High-spatial resolution immunoEM was used to interrogate the subcellular localization of C1q in aged macaque layer III dlPFC and aged rat layer III mPFC. co-IP techniques quantified protein-protein interactions for C1q and proteins associated with excitatory and inhibitory synapses in macaque dlPFC., Results: C1q levels were markedly increased in the aged macaque dlPFC. Ultrastructural localization found the expected C1q localization in glia, including those ensheathing synapses, but also revealed extensive localization within neurons. C1q was found near synapses, within terminals and in spines, but was also observed in dendrites, often near abnormal mitochondria. Similar analyses in aging rat mPFC corroborated the findings in rhesus macaques. C1q protein increasingly associated with PSD95 with age in macaque, consistent with its synaptic localization as evidenced by EM., Conclusions: These findings reveal novel, intra-neuronal distribution patterns for C1q in the aging primate cortex, including evidence of C1q in dendrites. They suggest that age-related changes in the dlPFC may increase C1q expression and synaptic tagging for glial phagocytosis, a possible mechanism for age-related degeneration.

The prefrontal cortex underlies our high order cognitive abilities and is the target of projections from many neuromodulatory nuclei. The dorsolateral prefrontal cortex is particularly critical for rule representation and working memory, or the ability to hold information "in mind" in the absence of sensory input. Emerging evidence supports a prominent and permissive role for acetylcholine in these excitatory circuits, through actions at cholinergic nicotinic receptors. Here we review the involvement of acetylcholine in working memory via actions at nicotinic receptors.

Although mouse models of Alzheimer's disease (AD) have provided tremendous breakthroughs, the etiology of later onset AD remains unknown. In particular, tau pathology in the association cortex is poorly replicated in mouse models. Aging rhesus monkeys naturally develop cognitive deficits, amyloid plaques, and the same qualitative pattern and sequence of tau pathology as humans, with tangles in the oldest animals. Thus, aging rhesus monkeys can play a key role in AD research. For example, aging monkeys can help reveal how synapses in the prefrontal association cortex are uniquely regulated compared to the primary sensory cortex in ways that render them vulnerable to calcium dysregulation and tau phosphorylation, resulting in the selective localization of tau pathology observed in AD. The ability to assay early tau phosphorylation states and perform high-quality immunoelectron microscopy in monkeys is a great advantage, as one can capture early-stage degeneration as it naturally occurs in situ. Our immunoelectron microscopy studies show that phosphorylated tau can induce an "endosomal traffic jam" that drives amyloid precursor protein cleavage to amyloid-β in endosomes. As amyloid-β increases tau phosphorylation, this creates a vicious cycle where varied precipitating factors all lead to a similar phenotype. These data may help explain why circuits with aggressive tau pathology (e.g., entorhinal cortex) may degenerate prior to producing significant amyloid pathology. Aging monkeys therefore can play an important role in identifying and testing potential therapeutics to protect the association cortex, including preventive therapies that are challenging to test in humans.

The prefrontal cortex (PFC) mediates higher cognition but is impaired by stress exposure when high levels of catecholamines activate calcium-cAMP-protein kinase A (PKA) signaling. The current study examined whether stress and increased cAMP-PKA signaling in rat medial PFC (mPFC) reduce pyramidal cell firing and impair working memory by activating KCNQ potassium channels. KCNQ2 channels were found in mPFC layers II/III and V pyramidal cells, and patch-clamp recordings demonstrated KCNQ currents that were increased by forskolin or by chronic stress exposure, and which were associated with reduced neuronal firing. Low dose of KCNQ blockers infused into rat mPFC improved cognitive performance and prevented acute pharmacological stress-induced deficits. Systemic administration of low doses of KCNQ blocker also improved performance in young and aged rats, but higher doses impaired performance and occasionally induced seizures. Taken together, these data demonstrate that KCNQ channels have powerful influences on mPFC neuronal firing and cognitive function, contributing to stress-induced PFC dysfunction., (© 2019 Published by Elsevier Inc.)