rudyvdbrink/CitationDatabase huggingface dataset:
Susceptibility to social pressure following ventromedial prefrontal cortex damage.
Social cognitive and affective neuroscience, 2015

Social pressure influences human behavior including risk taking, but the psychological and neural underpinnings of this process are not well understood. We used the human lesion method to probe the role of ventromedial prefrontal cortex (vmPFC) in resisting adverse social pressure in the presence of risk. Thirty-seven participants (11 with vmPFC damage, 12 with brain damage outside the vmPFC and 14 without brain damage) were tested in driving simulator scenarios requiring left-turn decisions across oncoming traffic with varying time gaps between the oncoming vehicles. Social pressure was applied by a virtual driver who honked aggressively from behind. Participants with vmPFC damage were more likely to select smaller and potentially unsafe gaps under social pressure, while gap selection by the comparison groups did not change under social pressure. Participants with vmPFC damage also showed prolonged elevated skin conductance responses (SCR) under social pressure. Comparison groups showed similar initial elevated SCR, which then declined prior to making left-turn decisions. The findings suggest that the vmPFC plays an important role in resisting explicit and immediately present social pressure with potentially negative consequences. The vmPFC appears to contribute to the regulation of emotional responses and the modulation of decision making to optimize long-term outcomes.
Conditional deletion of Id2 or Notch1 in oligodendrocyte progenitor cells does not ameliorate disease outcome in SOD1
Neurobiology of aging, 2018

Oligodendrocytes are essential for structural and trophic support of motor axons. Their impairment has been implicated in amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder of motor neurons. Oligodendrocyte progenitor cells fail to differentiate into mature oligodendrocytes and thereby jeopardize the health of motor neurons. Here, we report that oligodendrocytic ablation of inhibitor of DNA binding 2 (Id2) or Notch receptor 1 (Notch1), 2 negative master modulators of oligodendrocyte differentiation, fails to alleviate oligodendrocyte dysfunction or alter disease outcome in a murine model of ALS. Our data suggest that these inhibitors are not suitable targets for intervention in ALS.
Pulse Pressure and Cognitive Decline in Stroke Patients With White Matter Changes.
Journal of clinical hypertension (Greenwich, Conn.), 2015

The authors hypothesized that both high and low pulse pressure (PP) may predict cognitive decline in stroke/transient ischemic attack (TIA) patients with white matter changes (WMCs). The authors prospectively followed up 406 ischemic stroke/TIA patients with confluent WMCs over 18 months. PP was measured at 3 to 6 months after stroke/TIA and categorized into four groups by quartile. Cognition was assessed 3 to 6 months and 15 to 18 months after stroke/TIA using the Clinical Dementia Rating and Mini-Mental State Examination (MMSE). Logistic regression showed that patients in the first quartile of PP had a 5.9-fold higher risk for developing cognitive decline than patients in the third quartile (odds ratio, 5.9; 95% confidence interval, 1.7-20.6), while patients in the fourth quartile had a 3.5-fold higher risk for cognitive decline than those in the third quartile (odds ratio, 3.5; 95% confidence interval, 1.0-12.4). This U-shaped relationship was also evident between PP and cognitive decline in MMSE, underlining the role of arterial stiffness and hypoperfusion in cognitive decline related to small vessel disease.
Genome-wide analysis suggests the importance of vascular processes and neuroinflammation in late-life antidepressant response.
Translational psychiatry, 2021

Antidepressant outcomes in older adults with depression is poor, possibly because of comorbidities such as cerebrovascular disease. Therefore, we leveraged multiple genome-wide approaches to understand the genetic architecture of antidepressant response. Our sample included 307 older adults (≥60 years) with current major depression, treated with venlafaxine extended-release for 12 weeks. A standard genome-wide association study (GWAS) was conducted for post-treatment remission status, followed by in silico biological characterization of associated genes, as well as polygenic risk scoring for depression, neurodegenerative and cerebrovascular disease. The top-associated variants for remission status and percentage symptom improvement were PIEZO1 rs12597726 (OR = 0.33 [0.21, 0.51], p = 1.42 × 10
Visual sense of number vs. sense of magnitude in humans and machines.
Scientific reports, 2020

Numerosity perception is thought to be foundational to mathematical learning, but its computational bases are strongly debated. Some investigators argue that humans are endowed with a specialized system supporting numerical representations; others argue that visual numerosity is estimated using continuous magnitudes, such as density or area, which usually co-vary with number. Here we reconcile these contrasting perspectives by testing deep neural networks on the same numerosity comparison task that was administered to human participants, using a stimulus space that allows the precise measurement of the contribution of non-numerical features. Our model accurately simulates the psychophysics of numerosity perception and the associated developmental changes: discrimination is driven by numerosity, but non-numerical features also have a significant impact, especially early during development. Representational similarity analysis further highlights that both numerosity and continuous magnitudes are spontaneously encoded in deep networks even when no task has to be carried out, suggesting that numerosity is a major, salient property of our visual environment.
Risk-taking behavior: dopamine D2/D3 receptors, feedback, and frontolimbic activity.
Cerebral cortex (New York, N.Y. : 1991), 2015

Decision-making involves frontolimbic and dopaminergic brain regions, but how prior choice outcomes, dopamine neurotransmission, and frontostriatal activity are integrated to affect choices is unclear. We tested 60 healthy volunteers using the Balloon Analogue Risk Task (BART) during functional magnetic resonance imaging. In the BART, participants can pump virtual balloons to increase potential monetary reward or cash out to receive accumulated reward; each pump presents greater risk and potential reward (represented by the pump number). In a separate session, we measured striatal D2/D3 dopamine receptor binding potential (BPND) with positron emission tomography in 13 of the participants. Losses were followed by fewer risky choices than wins; and during risk-taking after loss, amygdala and hippocampal activation exhibited greater modulation by pump number than after a cash-out event. Striatal D2/D3 BPND was positively related to the modulation of ventral striatal activation when participants decided to cash out and negatively to the number of pumps in the subsequent trial; but negatively related to the modulation of prefrontal cortical activation by pump number when participants took risk, and to overall earnings. These findings provide in vivo evidence for a potential mechanism by which dopaminergic neurotransmission may modulate risk-taking behavior through an interactive system of frontal and striatal activity.
Intrinsic functional connectivity between amygdala and hippocampus during rest predicts enhanced memory under stress.
Psychoneuroendocrinology, 2017

Declarative memories of stressful events are less prone to forgetting than mundane events. Animal research has demonstrated that such stress effects on consolidation of hippocampal-dependent memories require the amygdala. In humans, it has been shown that during learning, increased amygdala-hippocampal interactions are related to more efficient memory encoding. Animal models predict that following learning, amygdala-hippocampal interactions are instrumental to strengthening the consolidation of such declarative memories. Whether this is the case in humans is unknown and remains to be empirically verified. To test this, we analyzed data from a sample of 120 healthy male participants who performed an incidental encoding task and subsequently underwent resting-state functional MRI in a stressful and a neutral context. Stress was assessed by measures of salivary cortisol, blood pressure, heart rate, and subjective ratings. Memory was tested afterwards outside of the scanner. Our data show that memory was stronger in the stress context compared to the neutral context and that stress-induced cortisol responses were associated with this memory enhancement. Interestingly, amygdala-hippocampal connectivity during post-encoding awake rest regardless of context (stress or neutral) was associated with the enhanced memory performance under stress. Thus, our findings are in line with a role for intrinsic functional connectivity during rest between the amygdala and the hippocampus in the state effects of stress on strengthening memory.
Carbonylation induces heterogeneity in cardiac ryanodine receptor function in diabetes mellitus.
Molecular pharmacology, 2012

Heart failure and arrhythmias occur at 3 to 5 times higher rates among individuals with diabetes mellitus, compared with age-matched, healthy individuals. Studies attribute these defects in part to alterations in the function of cardiac type 2 ryanodine receptors (RyR2s), the principal Ca(2+)-release channels on the internal sarcoplasmic reticulum (SR). To date, mechanisms underlying RyR2 dysregulation in diabetes remain poorly defined. A rat model of type 1 diabetes, in combination with echocardiography, in vivo and ex vivo hemodynamic studies, confocal microscopy, Western blotting, mass spectrometry, site-directed mutagenesis, and [(3)H]ryanodine binding, lipid bilayer, and transfection assays, was used to determine whether post-translational modification by reactive carbonyl species (RCS) represented a contributing cause. After 8 weeks of diabetes, spontaneous Ca(2+) release in ventricular myocytes increased ~5-fold. Evoked Ca(2+) release from the SR was nonuniform (dyssynchronous). Total RyR2 protein levels remained unchanged, but the ability to bind the Ca(2+)-dependent ligand [(3)H]ryanodine was significantly reduced. Western blotting and mass spectrometry revealed RCS adducts on select basic residues. Mutation of residues to delineate the physiochemical impact of carbonylation yielded channels with enhanced or reduced cytoplasmic Ca(2+) responsiveness. The prototype RCS methylglyoxal increased and then decreased the RyR2 open probability. Methylglyoxal also increased spontaneous Ca(2+) release and induced Ca(2+) waves in healthy myocytes. Treatment of diabetic rats with RCS scavengers normalized spontaneous and evoked Ca(2+) release from the SR, reduced carbonylation of RyR2s, and increased binding of [(3)H]ryanodine to RyR2s. From these data, we conclude that post-translational modification by RCS contributes to the heterogeneity in RyR2 activity that is seen in experimental diabetes.
The PDE4 inhibitor HT-0712 improves hippocampus-dependent memory in aged mice.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2014

Aging is associated with declines in memory and cognitive function. Here, we evaluate the effects of HT-0712 on memory formation and on cAMP response element-binding protein (CREB)-regulated genes in aged mice. HT-0712 enhanced long-term memory formation in normal young mice at brain concentrations similar to those found to increase CRE-mediated gene expression in hippocampal neurons. Aged mice showed significantly poorer contextual and trace conditioning compared with young-adult mice. In aged mice, a single injection of HT-0712 significantly boosted contextual and trace long-term memory. Additional effects of HT-0712 were seen in a spatial memory task. Our parallel biochemical experiments revealed that inductions of the CREB-regulated genes, cFos, Zif268, and Bdnf, after fear conditioning were diminished in aged mice. HT-0712 facilitated expression of these CREB-regulated genes in aged hippocampus, indicating that the drug engages a CREB-regulated mechanism in vivo. These findings corroborate and extend our previous results on the mechanism of action of HT-0712 and its efficacy to enhance memory formation. Our data also indicate that HT-0712 may be effective to treat age-associated memory impairment in humans.
Effect of informational content of noise on speech representation in the aging midbrain and cortex.
Journal of neurophysiology, 2016

The ability to understand speech is significantly degraded by aging, particularly in noisy environments. One way that older adults cope with this hearing difficulty is through the use of contextual cues. Several behavioral studies have shown that older adults are better at following a conversation when the target speech signal has high contextual content or when the background distractor is not meaningful. Specifically, older adults gain significant benefit in focusing on and understanding speech if the background is spoken by a talker in a language that is not comprehensible to them (i.e., a foreign language). To understand better the neural mechanisms underlying this benefit in older adults, we investigated aging effects on midbrain and cortical encoding of speech when in the presence of a single competing talker speaking in a language that is meaningful or meaningless to the listener (i.e., English vs. Dutch). Our results suggest that neural processing is strongly affected by the informational content of noise. Specifically, older listeners' cortical responses to the attended speech signal are less deteriorated when the competing speech signal is an incomprehensible language rather than when it is their native language. Conversely, temporal processing in the midbrain is affected by different backgrounds only during rapid changes in speech and only in younger listeners. Additionally, we found that cognitive decline is associated with an increase in cortical envelope tracking, suggesting an age-related over (or inefficient) use of cognitive resources that may explain their difficulty in processing speech targets while trying to ignore interfering noise.
High-resolution ultramicroscopy of the developing and adult nervous system in optically cleared Drosophila melanogaster.
Nature communications, 2018

The fruit fly, Drosophila melanogaster, is an important experimental model to address central questions in neuroscience at an organismic level. However, imaging of neural circuits in intact fruit flies is limited due to structural properties of the cuticle. Here we present a novel approach combining tissue clearing, ultramicroscopy, and data analysis that enables the visualisation of neuronal networks with single-cell resolution from the larval stage up to the adult Drosophila. FlyClear, the signal preserving clearing technique we developed, stabilises tissue integrity and fluorescence signal intensity for over a month and efficiently removes the overall pigmentation. An aspheric ultramicroscope set-up utilising an improved light-sheet generator allows us to visualise long-range connections of peripheral sensory and central neurons in the visual and olfactory system. High-resolution 3D reconstructions with isotropic resolution from entire GFP-expressing flies are obtained by applying image fusion from orthogonal directions. This methodological integration of novel chemical, optical, and computational techniques allows a major advance in the analysis of global neural circuit organisation.
Ins and outs of cerebellar modules.
Cerebellum (London, England), 2011

The modular concept of cerebellar connections has been advocated in the lifetime work of Jan Voogd. In this concept, a cerebellar module is defined as the conglomerate of one or multiple and non-adjacent, parasagittally arranged zones of Purkinje cells, their specific projection to a well-defined region of the cerebellar nuclei, and the climbing fiber input to these zones by a well-defined region of the inferior olivary complex. The modular organization of these olivo-cortico-nuclear connections is further exemplified by matching reciprocal connections between inferior olive and cerebellar nuclei. Because the different regions of the cerebellar nuclei show highly specific output patterns, cerebellar modules have been suggested to constitute functional entities. This idea is strengthened by the observation that anatomically defined modules adhere to the distribution of chemical markers in the cerebellar cortex suggesting that modules not only differ in their input and output relations but also may differ in operational capabilities. Here, I will briefly review some recent data on the establishment of cerebellar modules in rats. Furthermore, some evidence will be shown suggesting that the other main afferent system (i.e., mossy fibers), at least to some extent, also adheres to the modular organization. Finally, using retrograde transneuronal tracing with rabies virus, some evidence will be provided that several cerebellar modules may be involved in the control of individual muscles.
Spinal fractures incurred by a fall from standing height.
Clinical neurology and neurosurgery, 2019

Falls from standing are common, particularly amongst the aging population, due to declining mobility, proprioception and vision. They are often complicated by fragility fractures, including vertebral fractures, that are associated with significant morbidity and may represent a pre-terminal condition with high one-year mortality rates.
Emergent elasticity in the neural code for space.
Proceedings of the National Academy of Sciences of the United States of America, 2018

Upon encountering a novel environment, an animal must construct a consistent environmental map, as well as an internal estimate of its position within that map, by combining information from two distinct sources: self-motion cues and sensory landmark cues. How do known aspects of neural circuit dynamics and synaptic plasticity conspire to accomplish this feat? Here we show analytically how a neural attractor model that combines path integration of self-motion cues with Hebbian plasticity in synaptic weights from landmark cells can self-organize a consistent map of space as the animal explores an environment. Intriguingly, the emergence of this map can be understood as an elastic relaxation process between landmark cells mediated by the attractor network. Moreover, our model makes several experimentally testable predictions, including (
Response dynamics of rat barrel cortex neurons to repeated sensory stimulation.
Scientific reports, 2017

Neuronal adaptation is a common feature observed at various stages of sensory processing. Here, we quantified the time course of adaptation in rat somatosensory cortex. Under urethane anesthesia, we juxta-cellularly recorded single neurons (n = 147) while applying a series of whisker deflections at various frequencies (2-32 Hz). For ~90% of neurons, the response per unit of time decreased with frequency. The degree of adaptation increased along the train of deflections and was strongest at the highest frequency. However, a subset of neurons showed facilitation producing higher responses to subsequent deflections. The response latency to consecutive deflections increased both for neurons that exhibited adaptation and for those that exhibited response facilitation. Histological reconstruction of neurons (n = 45) did not reveal a systematic relationship between adaptation profiles and cell types. In addition to the periodic stimuli, we applied a temporally irregular train of deflections with a mean frequency of 8 Hz. For 70% of neurons, the response to the irregular stimulus was greater than that of the 8 Hz regular. This increased response to irregular stimulation was positively correlated with the degree of adaptation. Altogether, our findings demonstrate high levels of diversity among cortical neurons, with a proportion of neurons showing facilitation at specific temporal intervals.
Drosophila QVR/SSS modulates the activation and C-type inactivation kinetics of Shaker K(+) channels.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2011

The quiver/sleepless (qvr/sss) gene encodes a small, glycosylphosphatidylinositol-anchored protein that plays a critical role in the regulation of sleep in Drosophila. Loss-of-function mutations in qvr/sss severely suppress sleep and effect multiple changes in in situ Shaker K(+) currents, including decreased magnitude, slower time-to-peak, and cumulative inactivation. Recently, we demonstrated that SLEEPLESS (SSS) protein modulates Shaker channel activity, possibly through a direct interaction at the plasma membrane. We show here that SSS accelerates the activation of heterologously expressed Shaker channels with no effect on deactivation or fast N-type inactivation. Furthermore, this SSS-induced acceleration is sensitive to the pharmacological disruption of lipid rafts and sufficiently accounts for the slower time-to-peak of in situ Shaker currents seen in qvr/sss mutants. We also find that SSS decreases the rate of C-type inactivation of heterologously expressed Shaker channels, providing a potential mechanism for the cumulative inactivation phenotype induced by qvr/sss loss-of-function mutations. Kinetic modeling based on the in vitro results suggests that the SSS-dependent regulation of channel kinetics accounts for nearly 40% of the decrease in Shaker current magnitude in flies lacking SSS. Sleep duration in qvr/sss-null mutants is restored to normal by a qvr/sss transgene that fully rescues the Shaker kinetic phenotypes but only partially rescues the decrease in current magnitude. Together, these results suggest that the role of SSS in the regulation of sleep in Drosophila correlates more strongly with the effects of SSS on Shaker kinetics than current magnitude.
Effects of ketamine on context-processing performance in monkeys: a new animal model of cognitive deficits in schizophrenia.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2013

Cognitive deficits are at the crux of why many schizophrenia patients have poor functional outcomes. One of the cognitive symptoms experienced by schizophrenia patients is a deficit in context processing, the ability to use contextual information stored in working memory to adaptively respond to subsequent stimuli. As such, context processing can be thought of as the intersection between working memory and executive control. Although deficits in context processing have been extensively characterized by neuropsychological testing in schizophrenia patients, they have never been effectively translated to an animal model of the disease. To bridge that gap, we trained monkeys to perform the same dot pattern expectancy (DPX) task, which has been used to measure context-processing deficits in human patients with schizophrenia. In the DPX task, the first stimulus in each trial provides the contextual information that subjects must remember in order to appropriately respond to the second stimulus in the trial. We found that administration of ketamine, an N-methyl-D-aspartate receptor antagonist, in monkeys caused a dose-dependent failure in context processing, replicating in monkeys the same specific pattern of errors committed by patients with schizophrenia when performing the same task. Therefore, our results provide the first evidence that context-processing dysfunction can be modeled in animals. Replicating a schizophrenia-like behavioral performance pattern in monkeys performing the same task used in humans provides a strong bridge to better understand the biological basis for this psychiatric disease and its cognitive manifestations using animal models.