The Dismissive Actually

This project is about giving in to the impulse of ideas. My mind is a little messy and cluttered, swirling with bits of stimuli. The spark of an idea happens when the bits collide. I prefer not to initiate or control the process so much as keep it fed and active. Through graphic design, I bear witness to these ideas, giving them form as a series of visible, tangible objects. Viewed comprehensively, the work establishes an ongoing chronicle of my creative life and mind

Surprisingly correct: Unexpectedness of observed actions activates the medial prefrontal cortex

Not only committing errors, but also observing errors has been shown to activate the dorsal medial prefrontal cortex, particularly BA 8 and adjacent rostral cingulate zone (RCZ). Currently, there is a debate on whether this activity reflects a response to the incorrectness of the committed action or to its unexpectedness. This article reports two studies investigating whether activity in BA 8/RCZ is due to the unexpectedness of observed errors or the incorrectness of the specific observed action. Both studies employed an action observation paradigm reliant on the observation of an actor tying sailing knots. The reported behavioral experiment delivered evidence that the paradigm successfully induced the expectation of incorrect actions as well as the expectation of correct actions. The functional magnetic resonance imaging study revealed that unexpectedly correct as well as unexpectedly incorrect actions activate the BA 8/RCZ. The same result was confirmed for a coordinate in the vicinity that has been previously reported to be activated in separate studies either by the error observation or by the unexpectedness of committed errors, and has been associated with the error-related negativity. The present results suggest that unexpectedness has an impact on the medial prefrontal correlate of observed errors

Cryo-EM structural studies of the agonist complexed human TRPV4 ion-channel reveals novel structural rearrangements resulting in an open-conformation

The human transient receptor potential vanilloid 4 (hTRPV4) ion channel plays a critical role in a variety of biological processes. Whilst the activation of hTRPV4 gating properties has been reported for a broad spectrum of stimuli, including synthetic 4α-phorbols, the molecular basis of the activation is poorly understood. Here we report the novel cryo-EM structure of the hTRPV4 determined in the presence of the archetypical phorbol acid agonist, 4α-PDD. Complementary mutagenesis experiments support the EM-identified binding site as well as allowing rationalization of disruptive mutants located outside of the 4α-PDD binding site. This work represents the first structural information of hTRPV4 in a ligand-induced open conformation. Together, our data reveal the underlying molecular mechanisms resulting in the opening of the central pore and ion-channel activation and provide a structural template for designing inhibitors targeting the open-state conformation of hTRPV4

The role of the anterior cingulate cortex in prediction error and signaling surprise

In the past two decades, reinforcement learning (RL) has become a popular framework for understanding brain function. A key component of RL models, prediction error, has been associated with neural signals throughout the brain, including subcortical nuclei, primary sensory cortices, and prefrontal cortex. Depending on the location in which activity is observed, the functional interpretation of prediction error may change: Prediction errors may reflect a discrepancy in the anticipated and actual value of reward, a signal indicating the salience or novelty of a stimulus, and many other interpretations. Anterior cingulate cortex (ACC) has long been recognized as a region involved in processing behavioral error, and recent computational models of the region have expanded this interpretation to include a more general role for the region in predicting likely events, broadly construed, and signaling deviations between expected and observed events. Ongoing modeling work investigating the interaction between ACC and additional regions involved in cognitive control suggests an even broader role for cingulate in computing a hierarchically structured surprise signal critical for learning models of the environment. The result is a predictive coding model of the frontal lobes, suggesting that predictive coding may be a unifying computational principle across the neocortex. This paper reviews the brain mechanisms responsible for surprise; focusing on the Anterior Cingulate Cortex (ACC), long-known to play a role in behavioral-error, with a recently-expanded role in predicting likely' events and signaling deviations between expected and observed events. It argues for ACC's role in in surprise and learning, based on recent modelling work. As such, the paper provides the neuroscience complement to the psychological and computational proposals of other papers in the volume

Tuning of synapse number, structure and function in the cochlea.

Cochlear inner hair cells (IHCs) transmit acoustic information to spiral ganglion neurons through ribbon synapses. Here we have used morphological and physiological techniques to ask whether synaptic mechanisms differ along the tonotopic axis and within IHCs in the mouse cochlea. We show that the number of ribbon synapses per IHC peaks where the cochlea is most sensitive to sound. Exocytosis, measured as membrane capacitance changes, scaled with synapse number when comparing apical and midcochlear IHCs. Synapses were distributed in the subnuclear portion of IHCs. High-resolution imaging of IHC synapses provided insights into presynaptic Ca2+ channel clusters and Ca2+ signals, synaptic ribbons and postsynaptic glutamate receptor clusters and revealed subtle differences in their average properties along the tonotopic axis. However, we observed substantial variability for presynaptic Ca2+ signals, even within individual IHCs, providing a candidate presynaptic mechanism for the divergent dynamics of spiral ganglion neuron spiking

Cohesin acetyltransferase Esco2 is a cell viability factor and is required for cohesion in pericentric heterochromatin

Genetic deletion of murine Esco2 (an acetylase known to establish cohesin during S-phase and genetically linked to Roberts syndrome) results in embryonic lethality that can be molecularly linked to novel and specific functions of Esco2 at pericentric heterochromatin

Long-term impacts of prenatal synthetic glucocorticoids exposure on functional brain correlates of cognitive monitoring in adolescence

The fetus is highly responsive to the level of glucocorticoids in the gestational environment. Perturbing glucocorticoids during fetal development could yield long-term consequences. Extending prior research about effects of prenatally exposed synthetic glucocorticoids (sGC) on brain structural development during childhood, we investigated functional brain correlates of cognitive conflict monitoring in term-born adolescents, who were prenatally exposed to sGC. Relative to the comparison group, behavioral response consistency (indexed by lower reaction time variability) and a brain correlate of conflict monitoring (the N2 event-related potential) were reduced in the sGC exposed group. Relatedly, source localization analyses showed that activations in the fronto-parietal network, most notably in the cingulate cortex and precuneus, were also attenuated in these adolescents. These regions are known to subserve conflict detection and response inhibition as well as top-down regulation of stress responses. Moreover, source activation in the anterior cingulate cortex correlated negatively with reaction time variability, whereas activation in the precuneus correlated positively with salivary cortisol reactivity to social stress in the sGC exposed group. Taken together, findings of this study indicate that prenatal exposure to sGC yields lasting impacts on the development of fronto-parietal brain functions during adolescence, affecting multiple facets of adaptive cognitive and behavioral control