When learning a new motor skill, people often must use trial and error to discover which movement is best. In the reinforcement learning framework, this concept is known as exploration and has been linked to increased movement variability in motor tasks. For locomotor tasks, however, increased variability decreases upright stability. As such, exploration during gait may jeopardize balance and safety, making reinforcement learning less effective. Therefore, we set out to determine if humans could acquire and retain a novel locomotor pattern using reinforcement learning alone. Young healthy male and female participants walked on a treadmill and were provided with binary reward feedback (indicated by a green checkmark on the screen) that was tied to a fixed monetary bonus, to learn a novel stepping pattern. We also recruited a comparison group who walked with the same novel stepping pattern but did so by correcting for target error, induced by providing real-time veridical visual feedback of steps and a targe...

Self-ordered sequencing is an important executive function involving planning and executing a series of steps to achieve goal-directed outcomes. The lateral frontal cortex is implicated in this behavior, but downstream striatal outputs remain relatively unexplored. We trained marmosets on a three-stimulus self-ordered spatial sequencing task using a touch-sensitive screen to explore the role of the caudate nucleus and putamen in random and fixed response arrays. By transiently blocking glutamatergic inputs to these regions, using intrastriatal CNQX microinfusions, we demonstrate that the caudate and putamen are both required for, but contribute differently to, flexible and fixed sequencing. CNQX into either the caudate or putamen impaired variable array accuracy, and infusions into both simultaneously elicited greater impairment. We demonstrated that continuous perseverative errors in variable array were caused by putamen infusions, likely due to interference with the putamen's established role in monitori...

Dopamine system dysfunction, observed in animal models with psychosis-like symptomatology, can be restored by targeting gamma-aminobutyric acid type A receptors (GABAARs) containing the α5, but not α1, subunit in the ventral hippocampus (vHipp). The reason for this discrepancy in efficacy remains elusive; however, one key difference is that gamma-aminobutyric acid type A receptors containing the α1 subunit (α1GABAARs) are primarily located in the synapse, whereas gamma-aminobutyric acid type A receptors containing the α5 subunit (α5GABAARs) are mostly extrasynaptic. To test whether receptor location is responsible for this difference in efficacy, we injected an siRNA into the vHipp to knock down radixin, a scaffolding protein that holds α5GABAARs in the extrasynaptic space. We then administered GL-II-73, a positive allosteric modulator of α5GABAARs (α5-PAM) known to reverse shock-induced deficits in dopamine system function, to determine if shifting α5GABAARs from the extrasynaptic space to the synapse wou...

In our continuous drive to increase the standards of statistical rigor in neuroscience, we, at eNeuro , have launched a series of initiatives aimed at refining how statistics are employed, reported, and interpreted in neuroscience (Bernard, 2019, 2021; Calin-Jageman and Cumming, 2019). The drive toward this enhancement stems, in part, from the ongoing challenge of reproducibility—a cornerstone of scientific integrity that, unfortunately, has been undermined by gaps in statistical literacy (Bernard, 2023). Statistics, a discipline with its unique complexities and nuances, extends far beyond mere number-crunching. My personal journey from grasping basic statistical concepts to applying …

The cortical visual area, V4, has been considered to code contours that contribute to the intermediate-level representation of objects. The neural responses to the complex contour-features intrinsic to natural contours are expected to clarify the essence of the representation. To approach the cortical coding of natural contours, we investigated the simultaneous coding of multiple contour-features in monkey ( Macaca fuscata ) V4 neurons and their population-level representation. A substantial number of neurons showed significant tuning for two or more features such as curvature and closure, indicating that a substantial number of V4 neurons simultaneously code multiple contour-features. A large portion of the neurons responded vigorously to acutely curved contours that surrounded the center of classical receptive field, suggesting that V4 neurons tend to code prominent features of object contours. The analysis of mutual information (MI) between the neural responses and each contour feature showed that the m...

Problematic alcohol consumption is associated with deficits in decision-making, and alterations in prefrontal cortex neural activity likely contributes. We hypothesized that differences in cognitive control would be evident between male Wistar rats and a model for genetic risk for alcohol use disorder (alcohol-preferring P rats). Cognitive control can be split into proactive and reactive components. Proactive control maintains goal-directed behavior independent of a stimulus whereas reactive control elicits goal-directed behavior at the time of a stimulus. We hypothesized that Wistars would show proactive control over alcohol-seeking whereas P rats would show reactive control over alcohol-seeking. Neural ensembles were recorded from prefrontal cortex during an alcohol seeking task that utilized two session types. On congruent sessions the CS+ was on the same side as alcohol access. Incongruent sessions presented alcohol opposite the CS+. Wistars, but not P rats, exhibited an increase in incorrect approache...

GPR4 is a proton-sensing G protein-coupled receptor implicated in many peripheral and central physiological processes. GPR4 expression has previously been assessed only via detection of the cognate transcript or indirectly, by use of fluorescent reporters. In this work, CRISPR/Cas9 knock-in technology was used to encode a hemagglutinin (HA) epitope tag within the endogenous locus of Gpr4 and visualize GPR4-HA in the mouse central nervous system using a specific, well characterized HA antibody; GPR4 expression was further verified by complementary Gpr4 mRNA detection. HA immunoreactivity was found in a limited set of brain regions, including in the retrotrapezoid nucleus (RTN), serotonergic raphe nuclei, medial habenula, lateral septum, and several thalamic nuclei. GPR4 expression was not restricted to cells of a specific neurochemical identity as it was observed in excitatory, inhibitory, and aminergic neuronal cell groups. HA immunoreactivity was not detected in brain vascular endothelium, despite clear e...

Daylight vision is mediated by cone photoreceptors in vertebrates, which synapse with bipolar cells (BCs) and horizontal (HCs) cells. This cone synapse is functionally and anatomically complex, connecting to 8 types of depolarizing BCs (DBCs) and 5 types of hyperpolarizing BCs (HBCs) in mice. The dendrites of DBCs and HCs cells make invaginating ribbon synapses with the cone axon terminal, while HBCs form flat synapses with the cone pedicles. The molecular architecture that underpins this organization is relatively poorly understood. To identify new proteins involved in synapse formation and function we used an unbiased proteomic approach and identified LRFN2 (leucine-rich repeat and fibronectin III domain-containing 2) as a component of the DBC signaling complex. LRFN2 is selectively expressed at cone terminals and co-localizes with PNA, and other DBC signalplex members. In LRFN2 deficient mice, the synaptic markers: LRIT3, ELFN2, mGluR6, TRPM1 and GPR179 are properly localized. Similarly, LRFN2 expressio...

Stroke damage to the primary visual cortex (V1) causes severe visual deficits, which benefit from perceptual retraining. However, whereas training with high-contrast stimuli can locally restore orientation and motion direction discrimination abilities at trained locations, it only partially restores luminance contrast sensitivity (CS). Recent work revealed that high-contrast discrimination abilities may be preserved in the blind field of some patients early after stroke. Here, we asked if CS for orientation and direction discrimination is similarly preserved inside the blind field, to what extent, and whether it could benefit from a visual training intervention. Thirteen subacute patients (<3 months post-V1-stroke) and 12 chronic patients (>6 months post-V1-stroke) were pre-tested, then trained to discriminate either orientation or motion direction of Gabor patches of progressively lower contrasts as their performance improved. At baseline, more subacute than chronic participants could correctly discrimina...

The type I transmembrane protein BT-IgSF is predominantly localized in the brain and testes. It belongs to the CAR subgroup of Ig cell adhesion proteins, that are hypothesized to regulate connexin expression or localization. Here, we studied the putative link between BT-IgSF and connexins in astrocytes, ependymal cells and neurons of the mouse. Global knockout of BT-IgSF caused an increase in the clustering of connexin43 (Gja1), but not of connexin30 (Gjb6), on astrocytes and ependymal cells. Additionally, knockout animals displayed reduced expression levels of connexin43 protein in the cortex and hippocampus. Importantly, analysis of biocytin spread in hippocampal or cortical slices from mature mice of either sex revealed a decrease in astrocytic cell-cell coupling in the absence of BT-IgSF. Blocking either protein biosynthesis or proteolysis showed that the lysosomal pathway increased connexin43 degradation in astrocytes. Localization of connexin43 in subcellular compartments was not impaired in astrocyt...