Non-linear synaptic integration in dendrites is a fundamental aspect of neural computation. One such key mechanism is the Ca2+ spike at the apical tuft of pyramidal neurons. Characterized by a plateau potential sustained for tens of milliseconds, the Ca2+ spike amplifies excitatory input, facilitates somatic action potentials, and promotes synaptic plasticity. Despite its essential role, the mechanisms regulating it are largely unknown. Using a compartmental model of a layer 5 pyramidal cell, we explored the plateau and termination phases of the Ca2+ spike under input current perturbations, long-step current-injections, and variations in the dendritic high-voltage-activated Ca2+ conductance (that occur during cholinergic modulation). We found that, surprisingly, timed excitatory input can shorten the Ca2+ spike duration while inhibitory input can either elongate or terminate it. A significant elongation also occurs when the CaHVA conductance is increased. To mechanistically understand these phenomena, we a...

Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent side effect of widely used platinum-based anti-cancer agents. There are few predictable risk factors to identify susceptible patients. Effective preventive measures or treatments are not available. Here, we have used a model of CIPN in Drosophila melanogaster to identify genetic changes that confer resistance to cisplatin-induced neuronal damage but not in the rapidly dividing cells of the ovary. The Drosophila strain attP40, used as a genetic background for creation of RNAi lines, is resistant to cisplatin damage compared to the similar attP2 background strain. attP40 flies have reduced mRNA expression of ND-13A, a component of the mitochondria electron transport chain complex I. Reduction of ND-13A via neuron-specific RNAi leads to resistance to the dose-dependent climbing deficiencies and neuronal apoptosis observed in control flies. These flies are also resistant to acute oxidative stress, suggesting a mechanism for resistance to cisplati...

The striatum’s complex microcircuit is made by connections within and between its D1- and D2-receptor expressing projection neurons and at least five species of interneuron. Precise knowledge of this circuit is likely essential to understanding striatum’s functional roles and its dysfunction in a wide range of movement and cognitive disorders. We introduce here a Bayesian approach to mapping neuron connectivity using intracellular recording data, which lets us simultaneously evaluate the probability of connection between neuron types, the strength of evidence for it, and its dependence on distance. Using it to synthesise a complete map of the mouse striatum, we find strong evidence for two asymmetries: a selective asymmetry of projection neuron connections, with D2 neurons connecting twice as densely to other projection neurons than do D1 neurons, but neither subtype preferentially connecting to another; and a length-scale asymmetry, with interneuron connection probabilities remaining non-negligible at mor...

Auditory stimuli are often rhythmic in nature. Brain activity synchronizes with auditory rhythms via neural entrainment, and entrainment seems to be beneficial for auditory perception. However, it is not clear to what extent neural entrainment in the auditory system is reliable over time – a necessary prerequisite for targeted intervention. The current study aimed to establish the reliability of neural entrainment over time and to predict individual differences in auditory perception from associated neural activity. Across two different sessions, human listeners (21 females, 17 males) detected silent gaps presented at different phase locations of a 2-Hz frequency modulated (FM) noise while EEG activity was recorded. As expected, neural activity was entrained by the 2-Hz FM noise. Moreover, gap detection was sinusoidally modulated by the phase of the 2-Hz FM into which the gap fell. Critically, both the strength of neural entrainment as well as the modulation of performance by the stimulus rhythm were highl...

Attention-deficit hyperactivity disorder (ADHD) in adults is understudied, especially regarding neural mechanisms such as oscillatory control of attention sampling. We report an EEG study of such cortical mechanisms, in ADHD-diagnosed adults during administration of TOVA (Test of Variables of Attention), a gold-standard continuous performance test for ADHD that measures the ability to sustain attention and inhibit impulsivity. We recorded 53 adults (28f, 25m, aged 18-60), and 18 matched healthy controls, using 128-channel EEG. We analysed sensor-space features established as neural correlates of attention: timing-sensitivity and phase-synchrony of response activations, and event-related (de)synchronisation (ERS/D) of alpha and theta frequency band activity; in frontal and parietal scalp regions. TOVA test performance significantly distinguished ADHD adults from neurotypical controls, in commission errors, RT variability and d’ (response sensitivity). The ADHD group showed significantly weaker target- and...

Neuronal remodeling after brain injury is essential for functional recovery. After unilateral cortical lesion, axons from the intact cortex ectopically project to the denervated midbrain, but the molecular mechanisms remain largely unknown. To address this issue, we examined gene expression profiles in denervated and intact mouse midbrains after hemispherectomy at early developmental stages using mice of either sex, when ectopic contralateral projection occurs robustly. The analysis showed that various axon growth-related genes were upregulated in the denervated midbrain, and most of these genes are reportedly expressed by glial cells. To identify the underlying molecules, the receptors for candidate upregulated molecules were knocked out in layer 5 projection neurons in the intact cortex, using the CRISPR/Cas9-mediated method, and axonal projection from the knocked-out cortical neurons was examined after hemispherectomy. We found that the ectopic projection was significantly reduced when integrin subunit ...

The synaptic balance between excitation and inhibition (E/I balance) is a fundamental principle of cortical circuits, and disruptions in E/I balance are commonly linked to cognitive deficits such as impaired decision making. Explanatory gaps remain in a mechanistic understanding of how E/I balance contributes to cognitive computations, and how E/I disruptions at the synaptic level can propagate to induce behavioral deficits. Here, we studied how E/I perturbations may impair perceptual decision making in a biophysically-based association cortical circuit model. We found that both elevating and lowering E/I ratio — via NMDA receptor hypofunction at inhibitory interneurons and excitatory pyramidal neurons, respectively — can similarly impair psychometric performance, following an inverted-U dependence. Nonetheless, these E/I perturbations differentially alter the process of evidence accumulation across time. Under elevated E/I ratio, decision making is impulsive, overweighting early evidence and underweightin...

The synaptic balance between excitation and inhibition (E/I balance) is a fundamental principle of cortical circuits, and disruptions in E/I balance are commonly linked to cognitive deficits such as impaired decision making. Explanatory gaps remain in a mechanistic understanding of how E/I balance contributes to cognitive computations, and how E/I disruptions at the synaptic level can propagate to induce behavioral deficits. Here, we studied how E/I perturbations may impair perceptual decision making in a biophysically-based association cortical circuit model. We found that both elevating and lowering E/I ratio — via NMDA receptor hypofunction at inhibitory interneurons and excitatory pyramidal neurons, respectively — can similarly impair psychometric performance, following an inverted-U dependence. Nonetheless, these E/I perturbations differentially alter the process of evidence accumulation across time. Under elevated E/I ratio, decision making is impulsive, overweighting early evidence and underweightin...

Bilateral cochlear implants (BI-CIs) or a CI for single-sided deafness (SSD-CI; one normally functioning acoustic ear) can partially restore spatial-hearing abilities, including sound localization and speech understanding in noise. For these populations, however, interaural place-of-stimulation mismatch can occur and thus diminish binaural sensitivity that relies on interaurally frequency-matched neurons. This study examined whether plasticity—reorganization of central neural pathways over time—can compensate for peripheral interaural place mismatch. We hypothesized differential plasticity across two systems: none for binaural processing but adaptation for pitch perception toward frequencies delivered by the specific electrodes. Interaural place mismatch was evaluated in 19 BI-CI and 23 SSD-CI human subjects (both sexes) using binaural processing (interaural-time-difference discrimination with simultaneous bilateral stimulation), pitch perception (pitch ranking for single electrodes or acoustic tones with ...

Neurons in the developing visual cortex undergo progressive functional maturation as indicated by the refinement of their visual feature selectivity. However, changes of the synaptic architecture underlying the maturation of spatial visual receptive fields (RFs) per se remain largely unclear. Here, loose-patch as well as single-unit recordings in layer 4 of mouse primary visual cortex (V1) of both sexes revealed that RF development following an eye-opening period is marked by an increased proportion of cortical neurons with spatially defined RFs, together with the increased signal-to-noise ratio of spiking responses. By exploring excitatory and inhibitory synaptic RFs with whole-cell voltage-clamp recordings, we observed a balanced enhancement of both synaptic excitation and inhibition, and while the excitatory subfield size remains relatively constant during development, the inhibitory subfield is broadened. This balanced developmental strengthening of excitatory and inhibitory synaptic inputs results in ...