The antidiabetic drug metformin has been shown to reduce pain hypersensitivity in preclinical models of chronic pain and in neuropathic pain in humans. Multiple intracellular pathways have been described as metformin targets. Among them, metformin is an activator of the adenosine 5′-monophosphate protein kinase that can in turn modulate the activity of the E3 ubiquitin ligase NEDD4-2 and thus post-translational expression of voltage-gated sodium channels (NaVs). In this study, we found that the bulk of the effect of metformin on Na1.7 is dependent on NEDD4-2. In HEK cells, the expression of NaV1.7 at the membrane fraction, obtained by a biotinylation approach, is only reduced by metformin when cotransfected with NEDD4-2. Similarly, in voltage-clamp recordings, metformin significantly reduced NaV1.7 current density when cotransfected with NEDD4-2. In mouse dorsal root ganglion (DRG) neurons, without changing the biophysical properties of NaV1.7, metformin significantly decreased NaV1.7 current densities, bu...

Limb apraxia (LA) refers to a high-order motor disorder characterized by the inability to reproduce transitive actions on commands or after observation. Studies demonstrate that action observation and action execution activate the same networks in the human brain, and provides an onlooker’s motor system with appropriate cognitive, motor and sensory-motor cues to flexibly implementing action-sequences and gestures. Tellingly, the temporal dynamics of action monitoring has never been explored in people suffering from LA. To fill this gap, we studied the electro-cortical signatures of error observation in human participants suffering from acquired left-brain lesions with (LA+) and without (LA–) LA, and in a group of healthy controls (H). EEG was acquired while participants observed from a first-person perspective (1PP) an avatar performing correct or incorrect reach-to-grasp a glass action in an immersive-virtual environment. Alterations of typical EEG signatures of error observation in time (early error posi...

Reaching movements are known to have large condition-independent (CI) neural activity and cyclic neural dynamics. A new precision center-out task was performed by rhesus macaques to test the hypothesis that cyclic, CI neural activity in the primary motor cortex (M1) occurs not only during initial reaching movements but also during subsequent corrective movements. Corrective movements were observed to be discrete with time courses and bell-shaped speed profiles similar to the initial movements. CI cyclic neural trajectories were similar and repeated for initial and each additional corrective submovement. The phase of the cyclic CI neural activity predicted the time of peak movement speed more accurately than regression of instantaneous firing rate, even when the subject made multiple corrective movements. Rather than being controlled as continuations of the initial reach, a discrete cycle of motor cortex activity encodes each corrective submovement.

Finding the link between behaviors and their regulatory molecular pathways is a major obstacle in treating neuropsychiatric disorders. The immediate early gene (IEG) EGR1 is implicated in the etiology of neuropsychiatric disorders, and is linked to gene pathways associated with social behavior. Despite extensive knowledge of EGR1 gene regulation at the molecular level, it remains unclear how EGR1 deficits might affect the social component of these disorders. Here, we examined the social behavior of zebrafish with a mutation in the homologous gene egr1 . Mutant fish exhibited reduced social approach and orienting, whereas other sensorimotor behaviors were unaffected. On a molecular level, expression of the dopaminergic biosynthetic enzyme, tyrosine hydroxylase (TH), was strongly decreased in TH-positive neurons of the anterior parvocellular preoptic nucleus. These neurons are connected with basal forebrain (BF) neurons associated with social behavior. Chemogenetic ablation of around 30% of TH-positive neuro...

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...

In a competitive game involving an animal and an opponent, the outcome is contingent on the choices of both players. To succeed, the animal must continually adapt to competitive pressure, or else risk being exploited and lose out on rewards. In this study, we demonstrate that head-fixed male mice can be trained to play the iterative competitive game “matching pennies” against a virtual computer opponent. We find that the animals’ performance is well described by a hybrid computational model that includes Q-learning and choice kernels. Comparing between matching pennies and a non-competitive two-armed bandit task, we show that the tasks encourage animals to operate at different regimes of reinforcement learning. To understand the involvement of neuromodulatory mechanisms, we measure fluctuations in pupil size and use multiple linear regression to relate the trial-by-trial transient pupil responses to decision-related variables. The analysis reveals that pupil responses are modulated by observable variables,...

In the olfactory bulb, mitral cells (MCs) display a spontaneous firing that is characterized by bursts of action potentials (APs) intermixed with silent periods. Intraburst firing frequency and duration are heterogeneous among MCs and increase with membrane depolarization. By using patch-clamp recording on rat slices, we dissected out the intrinsic properties responsible for this bursting activity. We showed that the threshold of AP generation dynamically changes as a function of the preceding trajectory of the membrane potential. In fact, the AP threshold became more negative when the membrane was hyperpolarized and had a recovery rate inversely proportional to the membrane repolarization rate. Such variations appeared to be produced by changes in the inactivation state of voltage-dependent Na+ channels. Thus, AP initiation was favored by hyperpolarizing events, such as negative membrane oscillations or inhibitory synaptic input. After the first AP, the following fast afterhyperpolarization (AHP) brought ...

Motor cortical neurons exhibit persistent selective activities (selectivity) during motor planning. Experimental perturbation of selectivity results in the failure of short-term memory retention and consequent behavioral biases, demonstrating selectivity as a neural characteristic of encoding previous sensory input or future action. However, even without experimental manipulation, animals occasionally fail to maintain short-term memory leading to erroneous choice. Here, we investigated neural substrates that lead to the incorrect formation of selectivity during short-term memory. We analyzed neuronal activities in anterior lateral motor cortex (ALM) of mice, a region known to be engaged in motor planning while mice performed the tactile delayed-response task. We found that highly selective neurons lost their selectivity while originally nonselective neurons showed selectivity during the error trials where mice licked toward incorrect direction. We assumed that those alternations would reflect changes in in...

Working memory, a core function underlying many higher-level cognitive processes, requires cooperation of multiple brain regions. White matter refers to myelinated axons, which are critical to interregional brain communication. Past studies on the association between white-matter integrity and working memory have yielded mixed findings. Using voxelwise tract-based spatial statistics analysis, we investigated this relationship in a sample of 328 healthy adults from 25 to 80 years of age. Given the important role of dopamine (DA) in working-memory functioning and white matter, we also analyzed the effects of dopamine-related genes on them. There were associations between white-matter integrity and working memory in multiple tracts, indicating that working-memory functioning relies on global connections between different brain areas across the adult life span. Moreover, a mediation analysis suggested that white-matter integrity contributes to age-related differences in working memory. Finally, there was an ef...

Survival for vertebrate animals is dependent on the ability to successfully find food, locate a mate, and avoid predation. Each of these behaviors requires motor control, which is set by a combination of kinematic properties. For example, the frequency and amplitude of motor output combine in a multiplicative manner to determine features of locomotion such as distance traveled, speed, force (thrust), and vigor. Although there is a good understanding of how different populations of excitatory spinal interneurons establish locomotor frequency, there is a less thorough mechanistic understanding for how locomotor amplitude is established. Recent evidence indicates that locomotor amplitude is regulated in part by a subset of functionally and morphologically distinct V2a excitatory spinal interneurons (Type II, nonbursting) in larval and adult zebrafish. Here, we provide direct evidence that most V3 interneurons (V3-INs), which are a developmentally and genetically defined population of ventromedial glutamatergi...