Repetition is an indispensable component of motor skill acquisition. However, it is unknown how consistent repeated movement patterns must be to engage an implicit “use-dependent” learning mechanism. In this Registered Report, we tackled this question through a combination of computational modeling, simulations, and behavioral experiments involving visually-guided treadmill walking. Our hypotheses were formalized by two distinct computational models: in the two-process Strategy plus Use-Dependent model, use-dependent learning is viewed as a slowly updating and slowly decaying bias in the direction of repeated movements. The Adaptive Bayesian model frames use-dependent learning as an emergent property of quickly adapting prior probabilities of target step lengths. Critically, the Adaptive Bayesian model is much more sensitive to variable practice than the Strategy plus Use-Dependent model. To test these hypotheses, human participants ( N  = 18, 10 females) learned a novel asymmetric stepping pattern under t...

Forming long-term memories is crucial for adaptive behavior and survival in changing environments. The molecular consolidation processes which underlie the formation of these long-term memories are dependent on protein synthesis in excitatory and SST-expressing neurons. A centrally important, parallel process to this involves the removal of the memory constraint quinone reductase 2 (QR2), which has been recently shown to enhance memory consolidation for novel experiences in the cortex and hippocampus, via redox modulation. However, it is unknown within which cell type in the cortex removal of QR2 occurs, nor how this affects neuronal function. Here, we use novel taste learning in the mouse anterior insular cortex (aIC) to show that similarly to mRNA translation, QR2 removal occurs in excitatory and SST-expressing neurons. Interestingly, both novel taste and QR2 inhibition reduce excitability specifically within SST, but not excitatory neurons. Furthermore, reducing QR2 expression in SST, but not in PV or e...

Striatal activity is necessary to initiate and execute sequences of actions. The main excitatory input to the striatum comes from the cortex. While it is hypothesized that motor and premotor cortico-striatal projections are important to guide striatal activity during the execution of sequences of actions, technical limitations have made this challenging to address. Here, we implemented a task in mice that allows for the study of different moments to execute a serial order sequence consisting of two subsequences of actions. Using this task, we performed electrophysiological recordings in the premotor (M2) and primary motor (M1) cortices, and state-dependent optogenetic inhibitions of their cortico-striatal projections. We show that while both M2 and M1 contain activity modulations related to the execution of self-paced sequences, mainly, the premotor cortico-striatal projections contribute to the proper execution/structuring of these sequences.

Dopaminergic modulation is essential for the control of voluntary movement; however, the role of dopamine in regulating the neural excitability of the primary motor cortex (M1) is not well understood. Here, we investigated two modes by which dopamine influences the input/output function of M1 neurons. To test the direct regulation of M1 neurons by dopamine, we performed whole-cell recordings of excitatory neurons and measured excitability before and after local, acute dopamine receptor blockade. We then determined whether chronic depletion of dopaminergic input to the entire motor circuit, via a mouse model of Parkinson’s disease, was sufficient to shift M1 neuron excitability. We show that D1 receptor (D1R) and D2R antagonism altered subthreshold and suprathreshold properties of M1 pyramidal neurons in a layer-specific fashion. The effects of D1R antagonism were primarily driven by changes to intrinsic properties, while the excitability shifts following D2R antagonism relied on synaptic transmission. In c...

Neurons are highly vulnerable to conditions of hypoxia-ischemia (HI) such as stroke or transient ischemic attacks. Recovery of cognitive and behavioral functions requires re-emergence of coordinated network activity, which, in turn, relies on the well-orchestrated interaction of pyramidal cells (PYRs) and interneurons. We therefore modelled HI in the mouse hippocampus, a particularly vulnerable region showing marked loss of PYR and fast-spiking interneurons (FSIs) after hypoxic-ischemic insults. Transient oxygen-glucose deprivation (OGD) in ex vivo hippocampal slices led to a rapid loss of neuronal activity and spontaneous network oscillations (sharp wave-ripple complexes; SPW-Rs), and to the occurrence of a spreading depolarization. Following reperfusion, both SPW-R and neuronal spiking resumed, but FSI activity remained strongly reduced compared with PYR. Whole-cell recordings in CA1 PYR revealed, however, a similar reduction of both EPSCs and IPSCs, leaving inhibition-excitation (I/E) balance unaltered....

Relapse is a major challenge to the treatment of substance use disorders. A progressive increase in cue-induced drug craving, termed incubation of craving, is observed after withdrawal from multiple drugs of abuse in humans and rodents. Incubation of cocaine craving involves the strengthening of excitatory synapses onto nucleus accumbens (NAc) medium spiny neurons via postsynaptic accumulation of high-conductance Ca2+-permeable AMPA receptors. This enhances reactivity to drug-associated cues and is required for the expression of incubation. Additionally, incubation of cocaine craving is associated with loss of the synaptic depression normally triggered by stimulation of metabotropic glutamate receptor 5 (mGlu5), leading to endocannabinoid production, and expressed presynaptically via cannabinoid receptor 1 activation. Previous studies have found alterations in mGlu5 and Homer proteins associated with the loss of this synaptic depression. Here we conducted coimmunoprecipitation studies to investigate associ...

Gustometers have made it possible to deliver liquids in functional magnetic resonance imaging (fMRI) settings for decades, and mouthpieces are a critical part of these taste delivery systems. Here, we propose an innovative 3D-printed fMRI mouthpiece inspired by children’s pacifiers, allowing human participants to swallow while lying down in an MRI scanner. We used a large sample to validate the effectiveness of our method. The results suggest that the mouthpiece can be used to deliver taste stimuli by showing significant clusters of activation in the insular and piriform cortex, which are regions that have been consistently identified in taste processing. This mouthpiece fulfills several criteria guaranteeing a gustatory stimulus of quality, making the delivery precise and reliable. Moreover, this new pacifier-shaped design is simple and cheap to manufacture, hygienic, comfortable to keep in the mouth, and flexible to use in diverse cases. We hope that this new method will promote and facilitate the study ...

Epilepsy affects 3.4 million people in the United States, and, despite the availability of numerous antiepileptic drugs, 36% of patients have uncontrollable seizures, which severely impact quality of life. High-frequency oscillations (HFOs) are a potential biomarker of epileptogenic tissue that could be useful in surgical planning. As a result, research into the efficacy of HFOs as a clinical tool has increased over the last 2 decades. However, detection and identification of these transient rhythms in intracranial electroencephalographic recordings remain time-consuming and challenging. Although automated detection algorithms have been developed, their results are widely inconsistent, reducing reliability. Thus, manual marking of HFOs remains the gold standard, and manual review of automated results is required. However, manual marking and review are time consuming and can still produce variable results because of their subjective nature and the limitations in functionality of existing open-source softwar...

Although we use our visual and tactile sensory systems interchangeably for object recognition on a daily basis, little is known about the mechanism underlying this ability. This study examined how 3D shape features of objects form two congruent and interchangeable visual and tactile perceptual spaces in healthy male and female participants. Since active exploration plays an important role in shape processing, a virtual reality environment was used to visually explore 3D objects called digital embryos without using the tactile sense. In addition, during the tactile procedure, blindfolded participants actively palpated a 3D-printed version of the same objects with both hands. We first demonstrated that the visual and tactile perceptual spaces were highly similar. We then extracted a series of 3D shape features to investigate how visual and tactile exploration can lead to the correct identification of the relationships between objects. The results indicate that both modalities share the same shape features to...

Two novel short-interval intracortical inhibition (SICI) protocols, assessing SICI across a range of interstimulus intervals (ISIs) using either parallel threshold-tracking transcranial magnetic stimulation (TT-TMS) or automated conventional TMS (cTMS), were recently introduced. However, the test-retest reliability of these protocols has not been investigated, which is important if they are to be introduced in the clinic. SICI was recorded in 18 healthy subjects using TT-TMS (T-SICI) and cTMS (A-SICI). All subjects were examined at four identical sessions, i.e., morning and afternoon sessions on 2 d, 5–7 d apart. Both SICI protocols were performed twice at each session by the same observer. In one of the sessions, another observer performed additional examinations. Neither intraobserver nor interobserver measures of SICI differed significantly between examinations, except for T-SICI at ISI 3 ms ( p  = 0.00035) and A-SICI at ISI 2.5 ms ( p  = 0.0103). Intraday reliability was poor-to-good for A-SICI and mod...