Faculty Bibliography

OBJECTIVE:The natural history and long-term durability of Guglielmi detachable coil (GDC) embolization is still unknown. We hypothesize a stepwise decrease in durability of embolized cerebral aneurysms as stratified by the Modified Raymond-Roy Classification (MRRC). METHODS:First-time GDC-embolized cerebral aneurysms were retrospectively reviewed from 2004 to 2015. Loss of durability (LOD) was defined by change in aneurysm size or patency seen on serial radiographic follow-up. Kaplan-Meier survival analysis was performed to evaluate embolization durability. Multivariate Cox regression modeling was used to assess baseline aneurysm and patient characteristics for their effect on LOD. RESULTS:A total of 427 patients with 443 aneurysms met the inclusion criteria. Overall, 89 (21%) aneurysms met LOD criteria. Grade 1 aneurysms had statistically significantly greater durability than did all other MRRC grades. Grade 3b aneurysms had significantly worse durability than did all other aneurysm grades. There was no difference in durability between grade 2 and 3a aneurysms. Of aneurysms with LOD, 26 (29%) experienced worsening of MRRC grade. Thirty-five (24%) initial MRRC grade 2, 72 (45%) initial MRRC grade 3a, and 6 (22%) initial MRRC grade 3b aneurysms progressed to MRRC grade 1 without retreatment. In our multivariate analysis, only initial MRRC grade was statistically significantly associated with treatment durability (P < 0.001). CONCLUSIONS:MRRC grade is independently associated with first-time GDC-embolized cerebral aneurysm durability. Achieving MRRC grade 1 occlusion outcome is significantly associated with greater long-term GDC durability. Although few aneurysms experience further growth and/or recanalization, most incompletely obliterated aneurysms tend to remain stable over time or even progress to occlusion. Grading scales such as the MRRC are useful for characterizing aneurysm occlusion but may lack sensitivity and specificity for characterizing changes in aneurysm morphology over time.

RATIONALE/BACKGROUND:Dopamine D2-like receptors (D2R) are important drug targets in schizophrenia and Parkinson's disease, but D2R ligands also cause cognitive inflexibility such as poor reversal learning. The specific role of D2R in reversal learning remains unclear. OBJECTIVES/OBJECTIVE:We tested the hypotheses that D2R agonism impairs reversal learning by blocking negative feedback and that antagonism of D1-like receptors (D1R) impairs learning from positive feedback. METHODS:Male Lister Hooded rats were trained on a novel visual reversal learning task. Performance on "probe trials", during which the correct or incorrect stimulus was presented with a third, probabilistically rewarded (50% of trials) and therefore intermediate stimulus, revealed individual learning curves for the processes of positive and negative feedback. The effects of D2R and D1R agonists and antagonists were evaluated. A separate cohort was tested on a spatial probabilistic reversal learning (PRL) task after D2R agonism. Computational reinforcement learning modelling was applied to choice data from the PRL task to evaluate the contribution of latent factors. RESULTS:D2R agonism with quinpirole dose-dependently impaired both visual reversal and PRL. Analysis of the probe trials on the visual task revealed a complete blockade of learning from negative feedback at the 0.25 mg/kg dose, while learning from positive feedback was intact. Estimated parameters from the model that best described the PRL choice data revealed a steep and selective decrease in learning rate from losses. D1R antagonism had a transient effect on the positive probe trials. CONCLUSIONS:D2R stimulation impairs reversal learning by blocking the impact of negative feedback.

Study of the origin and development of cerebellar tumours has been hampered by the complexity and heterogeneity of cerebellar cells that change over the course of development. Here we use single-cell transcriptomics to study more than 60,000 cells from the developing mouse cerebellum and show that different molecular subgroups of childhood cerebellar tumours mirror the transcription of cells from distinct, temporally restricted cerebellar lineages. The Sonic Hedgehog medulloblastoma subgroup transcriptionally mirrors the granule cell hierarchy as expected, while group 3 medulloblastoma resembles Nestin⁺ stem cells, group 4 medulloblastoma resembles unipolar brush cells, and PFA/PFB ependymoma and cerebellar pilocytic astrocytoma resemble the prenatal gliogenic progenitor cells. Furthermore, single-cell transcriptomics of human childhood cerebellar tumours demonstrates that many bulk tumours contain a mixed population of cells with divergent differentiation. Our data highlight cerebellar tumours as a disorder of early brain development and provide a proximate explanation for the peak incidence of cerebellar tumours in early childhood.

Using clever experimental design and exploiting the high temporal resolution power of magnetoencephalography, Liu et al. show in humans how "offline" reactivation of brain patterns allows the abstraction of new knowledge from previous experience. The key mechanism may involve hippocampal sharp-wave ripples.

G protein-coupled receptors (GPCRs) are membrane proteins that play important roles in biology. However, our understanding of their function in complex living systems is limited because we lack tools that can target individual receptors with sufficient precision. State-of-the-art approaches, including DREADDs, optoXRs, and PORTL gated-receptors, control GPCR signaling with molecular, cell type, and temporal specificity. Nonetheless, these tools are based on engineered non-native proteins that may (i) express at nonphysiological levels, (ii) localize and turnover incorrectly, and/or (iii) fail to interact with endogenous partners. Alternatively, membrane-anchored ligands (t-toxins, DARTs) target endogenous receptors with molecular and cell type specificity but cannot be turned on and off. In this study, we used a combination of chemistry, biology, and light to control endogenous metabotropic glutamate receptor 2 (mGluR2), a Family C GPCR, in primary cortical neurons. mGluR2 was rapidly, reversibly, and selectively activated with photoswitchable glutamate tethered to a genetically targeted-plasma membrane anchor (membrane anchored Photoswitchable Orthogonal Remotely Tethered Ligand; maPORTL). Photoactivation was tuned by adjusting the length of the PORTL as well as the expression level and geometry of the membrane anchor. Our findings provide a template for controlling endogenous GPCRs with cell type specificity and high spatiotemporal precision.

Failure of anti-amyloid-β peptide (Aβ) therapies against Alzheimer's disease (AD), a neurodegenerative disorder characterized by high amounts of the peptide in the brain, raised the question of the physiological role of Aβ released at low concentrations in the healthy brain. To address this question, we studied the presynaptic and postsynaptic mechanisms underlying the neuromodulatory action of picomolar amounts of oligomeric Aβ₄₂ (oAβ₄₂) on synaptic glutamatergic function in male and female mice. We found that 200 pm oAβ₄₂ induces an increase of frequency of miniature EPSCs and a decrease of paired pulse facilitation, associated with an increase in docked vesicle number, indicating that it augments neurotransmitter release at presynaptic level. oAβ₄₂ also produced postsynaptic changes as shown by an increased length of postsynaptic density, accompanied by an increased expression of plasticity-related proteins such as cAMP-responsive element binding protein phosphorylated at Ser133, calcium-calmodulin-dependent kinase II phosphorylated at Thr286, and brain-derived neurotrophic factor, suggesting a role for Aβ in synaptic tagging. These changes resulted in the conversion of early into late long-term potentiation through the nitric oxide/cGMP/protein kinase G intracellular cascade consistent with a cGMP-dependent switch from short- to long-term memory observed in vivo after intrahippocampal administration of picomolar amounts of oAβ₄₂ These effects were present upon extracellular but not intracellular application of the peptide and involved α7 nicotinic acetylcholine receptors. These observations clarified the physiological role of oAβ₄₂ in synaptic function and memory formation providing solid fundamentals for investigating the pathological effects of high Aβ levels in the AD brains.SIGNIFICANCE STATEMENT High levels of oligomeric amyloid-β₄₂ (oAβ₄₂) induce synaptic dysfunction leading to memory impairment in Alzheimer's disease (AD). However, at picomolar concentrations, the peptide is needed to ensure long-term potentiation (LTP) and memory. Here, we show that extracellular 200 pm oAβ₄₂ concentrations increase neurotransmitter release, number of docked vesicles, postsynaptic density length, and expression of plasticity-related proteins leading to the conversion of early LTP into late LTP and of short-term memory into long-term memory. These effects require α7 nicotinic acetylcholine receptors and are mediated through the nitric oxide/cGMP/protein kinase G pathway. The knowledge of Aβ function in the healthy brain might be useful to understand the causes leading to its increase and detrimental effect in AD.

Complex dendrites in general present formidable challenges to understanding neuronal information processing. To circumvent the difficulty, a prevalent viewpoint simplifies the neuronal morphology as a point representing the soma, and the excitatory and inhibitory synaptic currents originated from the dendrites are treated as linearly summed at the soma. Despite its extensive applications, the validity of the synaptic current description remains unclear, and the existing point neuron framework fails to characterize the spatiotemporal aspects of dendritic integration supporting specific computations. Using electrophysiological experiments, realistic neuronal simulations, and theoretical analyses, we demonstrate that the traditional assumption of linear summation of synaptic currents is oversimplified and underestimates the inhibition effect. We then derive a form of synaptic integration current within the point neuron framework to capture dendritic effects. In the derived form, the interaction between each pair of synaptic inputs on the dendrites can be reliably parameterized by a single coefficient, suggesting the inherent low-dimensional structure of dendritic integration. We further generalize the form of synaptic integration current to capture the spatiotemporal interactions among multiple synaptic inputs and show that a point neuron model with the synaptic integration current incorporated possesses the computational ability of a spatial neuron with dendrites, including direction selectivity, coincidence detection, logical operation, and a bilinear dendritic integration rule discovered in experiment. Our work amends the modeling of synaptic inputs and improves the computational power of a modeling neuron within the point neuron framework.

INTRODUCTION/BACKGROUND:Downregulation of brain-derived neurotrophic factor (BDNF) and its cognate neurotrophin receptor, TrkB, were observed during the progression of dementia, but whether the Alzheimer's disease (AD) pathological lesions diffuse plaques, (DPs), neuritic plaques (NPs), and neurofibrillary tangles (NFTs) are related to this alteration remains to be clarified. METHODS:Negative binomial (NB) regressions were performed using gene expression data accrued from a single population of CA1 pyramidal neurons and regional hippocampal dissections obtained from participants in the Rush Religious Orders Study (RROS). RESULTS:Downregulation of Bdnf is independently associated with increased entorhinal cortex NPs. Downregulation of TrkB is independently associated with increased entorhinal cortex NFTs and CA1 NPs during the progression of AD. DISCUSSION/CONCLUSIONS:Results indicate that BDNF and TrkB dysregulation contribute to AD neuropathology, most notably hippocampal NPs and NFTs. These data suggest attenuating BDNF/TrkB signaling deficits either at the level of BDNF, TrkB, or downstream of TrkB signaling may abrogate NPs and/or NFTs.

Recent studies have expanded our understanding of sleep regulation by elucidating multiple neural circuits that promote sleep. In this issue of Neuron, Ma et al. (2019) identify a novel thalamo-amygdalar circuit which uses neurotensin to initiate and sustain NREM sleep.

Decisions under uncertainty distinguish between those made under risk (known probabilities) and those made under ambiguity (unknown probabilities). Despite widespread interest in decisions under uncertainty and the successful documentation that these distinct psychological constructs profoundly-and differentially-impact behavior, research has not been able to systematically converge on which brain regions are functionally involved in processing risk and ambiguity. We merge a lesion approach with computational modeling and simultaneous measurement of the arousal response to investigate the impact the medial prefrontal cortex (mPFC), lateral prefrontal cortex (lPFC), and amygdala have on decisions under uncertainty. Results reveal that the lPFC acts as a unitary system for processing uncertainty: Lesions to this region disrupted the relationship between arousal and choice, broadly increasing both risk and ambiguity seeking. In contrast, the mPFC and amygdala appeared to play no role in processing risk, and the mPFC only had a tenuous relationship with ambiguous uncertainty. Together, these findings reveal that only the lPFC plays a global role in processing the highly aversive nature of uncertainty.