The architecture of the efferent auditory system enables prioritization of strongly overlapping spatiotemporal cochlear activation patterns elicited by relevant and irrelevant inputs. So far, attempts at finding such attentional modulations of cochlear activity delivered indirect insights in humans or required direct recordings in animals. The extent to which spiral ganglion cells forming the human auditory nerve are sensitive to selective attention remains largely unknown. We investigated this question by testing the effects of attending to either the auditory or visual modality in human cochlear implant (CI) users (3 female, 13 male). Auditory nerve activity was directly recorded with standard CIs during a silent (anticipatory) cue-target interval. When attending the upcoming auditory input, ongoing auditory nerve activity within the theta range (5-8 Hz) was enhanced. Crucially, using the broadband signal (4-25 Hz), a classifier was even able to decode the attended modality from single-trial data. Follow...

Response nonlinearities are ubiquitous throughout the brain, especially within sensory cortices where changes in stimulus intensity typically produce compressed responses. Although this relationship is well established in electrophysiological measurements, it remains controversial whether the same nonlinearities hold for population-based measurements obtained with human fMRI. We propose that these purported disparities are not contingent on measurement type and are instead largely dependent on the visual system state at the time of interrogation. We show that deploying a contrast adaptation paradigm permits reliable measurements of saturating sigmoidal contrast response functions (10 participants, 7 female). When not controlling the adaptation state, our results coincide with previous fMRI studies, yielding nonsaturating, largely linear contrast responses. These findings highlight the important role of adaptation in manifesting measurable nonlinear responses within human visual cortex, reconciling discrepa...

How do animals adopt a given behavioral strategy to solve a recurrent problem when several effective strategies are available to reach the goal? Here we provide evidence that striatal cholinergic interneurons (SCINs) modulate their activity when mice must select between different strategies with similar goal-reaching effectiveness. Using a cell type-specific transgenic murine system, we show that adult SCIN ablation impairs strategy selection in navigational tasks where a goal can be independently achieved by adopting an allocentric or egocentric strategy. SCIN-depleted mice learn to achieve the goal in these tasks, regardless of their appetitive or aversive nature, in a similar way as controls. However, they cannot shift away from their initially adopted strategies, as control mice do, as training progresses. Our results indicate that SCINs are required for shaping the probability function used for strategy selection as experience accumulates throughout training. Thus, SCINs may be critical for the resolu...

Amanda Jiménez-Pompa, Sara Sanz-Lázaro, Romidan Ewere Omodolor, José Medina-Polo, Carmen González-Enguita, et al. (see pages [1173–1183][1]) Nicotinic acetylcholine receptors (nAChRs) are ligand-gated cation channels with roles throughout the CNS and peripheral nervous system, as well as in

Many fundamental human behaviors contain multiple sequences performed to reach a desired outcome, such as cooking. Reward is inherently associated with sequence completion and has been shown to generally enhance cognitive control. However, the impact of reward on cognitive sequence processing remains unexplored. To address this key question, we focused on the rostrolateral prefrontal cortex (RLPFC). This area is necessary and exhibits increasing (“ramping”) activation during sequences, a dynamic that may be related to reward processing in other brain regions. To separate these dynamics, we designed a task where reward was only provided after multiple four-item sequences (“iterations”), rather than each individual sequence. Using fMRI in humans, we investigated three possible interactions of reward and sequential control signals in RLPFC: (1) with the visibility of sequential cues, i.e. memory; (2) equally across individual sequence iterations; and (3) differently across individual sequence iterations (e.g....

Tight regulation of neuronal Zn2+ is critical for physiological function. Multiple Zn2+ transporters are expressed in the brain, yet their spatial distribution and distinct roles are largely unknown. Here, we show developmental regulation of the expression of Zn2+ transporters ZIP1 and ZIP3 in mouse hippocampal neurons, corresponding to previously described increase in neuronal vesicular Zn2+ during the first postnatal month. Rates of Zn2+ uptake in cultured mouse hippocampal neurons, monitored using FluoZin-3 fluorescence, were higher in mature neurons, which express higher levels of ZIP1 and ZIP3. Zn2+ uptake was attenuated by approximately 50% following silencing of either ZIP1 or ZIP3. Expression of both ZIP1 and ZIP3 was ubiquitous on somas and most neuronal processes in the cultured neurons. In contrast, we observed distinct localization of the transporters in adult mouse hippocampal brain, with ZIP1 predominantly expressed in the CA3 stratum pyramidale, and ZIP3 primarily localized to the stratum lu...

Dysregulation of autophagic pathways leads to accumulation of abnormal proteins and damaged organelles in many neurodegenerative disorders, including Parkinson’s disease (PD) and Lewy body dementia (LBD). Autophagy-related dysfunction may also trigger secretion and spread of misfolded proteins such as α-synuclein (α-syn), the major misfolded protein found in PD/LBD. However, the mechanism underlying these phenomena remains largely unknown. Here, we used cell-based models, including human induced pluripotent stem cell (hiPSC)-derived neurons, CRISPR/Cas9 technology, and male transgenic PD/LBD mice, plus vetting in human postmortem brains (both male and female). We provide mechanistic insight into this pathological pathway. We find that aberrant S-nitrosylation of the autophagic adaptor protein p62 causes inhibition of autophagic flux and intracellular build-up of misfolded proteins, with consequent secretion resulting in cell-to-cell spread. Thus, our data show that pathological protein S-nitrosylation of p...

Bayesian inference provides an elegant theoretical framework for understanding the characteristic biases and discrimination thresholds in visual speed perception. However, the framework is difficult to validate due to its flexibility and the fact that suitable constraints on the structure of the sensory uncertainty have been missing. Here, we demonstrate that a Bayesian observer model constrained by efficient coding not only well explains human visual speed perception but also provides an accurate quantitative account of the tuning characteristics of neurons known for representing visual speed. Specifically, we found that the population coding accuracy for visual speed in area MT (“neural prior”) is precisely predicted by the power-law, slow-speed prior extracted from fitting the Bayesian model to psychophysical data (“behavioral prior”) to the point that the two priors are indistinguishable in a cross-validation model comparison. Our results demonstrate a quantitative validation of the Bayesian observer m...

Dendrite and axon arbor sizes are critical to neuronal function and vary widely between different neuron types. The relative dendrite and axon sizes of synaptic partners control signal convergence and divergence in neural circuits. The developmental mechanisms that determine cell-type-specific dendrite and axon size and match synaptic partners' arbor territories remain obscure. Here, we discover that retinal horizontal cells express the leucine-rich repeat domain cell adhesion molecule AMIGO1. Horizontal cells provide pathway-specific feedback to photoreceptors: horizontal cell axons to rods and horizontal cell dendrites to cones. AMIGO1 selectively expands the size of horizontal cell axons. When Amigo1 is deleted in all or individual horizontal cells of either sex, their axon arbors shrink. By contrast, horizontal cell dendrites and synapse formation of horizontal cell axons and dendrites are unaffected by AMIGO1 removal. The dendrites of rod bipolar cells, which do not express AMIGO1, shrink in parallel ...