It has been suggested that the dorsomedial striatum (DMS) is engaged in the early stages of motor learning for goal-directed actions, whereas at later stages, control is transferred to the dorsolateral striatum (DLS), a process that enables learned motor actions to become a skill or habit. It is not known if these striatal regions are simultaneously active while the expertise is acquired. To address this question, we developed a mouse “treadmill training task” that tracks changes in mouse locomotor coordination during running practice and simultaneously provides a means to measure local neuronal activity using photometry. To measure change in motor coordination over treadmill practice sessions, we used DeepLabCut and custom-built code to analyze body position and paw movements. By evaluating improvements in motor coordination during training with simultaneous neuronal calcium activity in the striatum, we found that DMS direct pathway neurons exhibited decreased activity as the mouse gained proficiency at r...

Thyroid hormones (THs), thyroxine (T4) and triiodothyronine (T3), regulate growth, metabolism, and neurodevelopment. THs secretion is controlled by the pituitary thyroid-stimulating hormone (TSH) and the hypothalamic-pituitary-thyroid (HPT) axis. The organic anion-transporting polypeptide 1C1 (OATP1C1/Slco1c1) and the monocarboxylate transporter 8 (MCT8/SLC16A2) actively transport THs, which bind to their nuclear receptors and induce gene expression. A mutation in OATP1C1 is associated with brain hypometabolism, gradual neurodegeneration, and impaired cognitive and motor functioning in adolescent patients. In order to understand the role of Oatp1c1 and the mechanisms of the disease, we profiled the transcriptome of oatp1c1 mutant ( oatp1c1-/- ) and mct8-/-xoatp1c1-/- adult male and female zebrafish brains. Among dozens of differentially expressed genes, agouti-related neuropeptide 1 ( agrp1 ) expression increased in oatp1c1-/- adult brains. Imaging in the hypothalamus revealed enhanced proliferation of Agr...

The human visual system consists of multiple topographic maps that extend from the early visual cortex (EVC) along the dorsal and ventral processing streams. Responses to illusory shapes within these maps have been demonstrated in the ventral stream areas, in particular the lateral occipital complex (LOC). Recently, the intraparietal sulcus (IPS) of the dorsal stream has been linked to the processing of illusory shapes defined by motion. It remains unclear whether the topographically organized parietal areas also respond to stationary illusory shapes, which would suggest their generic role in representing illusory content. In the current study we measured brain responses using fMRI while 30 human participants (12 male) observed flickering inducers around the fixation task. The inducers either formed an illusory diamond in the center, a triangle in the left or right hemifield, or were inverted such that no illusory figure was formed. We compared responses of parietal regions IPS0-IPS5 and SPL1 to each illus...

An increasing number of studies have shown that cross-modal interaction can occur in early sensory cortices. Yet, how neurons in sensory cortices integrate multisensory cues in perceptual tasks and to what extent this influences behavior is largely unclear. To investigate, we examined visual modulation of auditory responses in the primary auditory cortex (A1) in a two-alternative forced-choice task. During the task, male rats were required to make a behavioral choice based on the pure tone frequency (low vs. high) of the self-triggered stimulus to get a water reward. The result showed that the presence of a noninformative visual cue did not uniformly influence auditory response, with frequently enhancing just one of them. Closely correlated with behavioral choice, the visual cue mainly enhanced responsiveness to the auditory cue indicating a movement direction contralateral to A1 recorded. Operating in this fashion afforded A1 neurons a superior capability to discriminate sound during multisensory trials. ...

In vitro and in vivo experimentation in the central nervous system are effective approaches to study its functioning. Manipulations in vitro are characterized by easy experimental control and stable experimental conditions. However, transferring these advantages to in vivo research remains technically and ethically challenging, preventing many research teams from acquiring critical recordings in their animal models. In order to transfer the benefits of in vitro experimentation to in vivo experimentation, we developed a suite of 3d-printed tools (a superfusion chamber with an independent brain presser and animal stand). Using the immature rat barrel cortex as a model, we show that our set of tools (further ’superfusion preparation’) provides stable conditions for electrophysiological and neuroimaging recordings in the neonatal rat neocortex in vivo . Highly correlated intra- and extracellular activity was recorded during spontaneous and evoked cortical activity, supporting the possibility of simultaneous lo...

Considerable evidence from mouse models and human postmortem tissue suggests loss of Muscleblind-like protein 2 (MBNL2) function in brain is a major driver of central nervous system symptoms in Myotonic Dystrophy Type 1 (DM1). Increased hypersomnia, fatigue, and surgical complications associated with general anesthesia suggest possible sensitivity to GABAergic inhibition in DM1. To test the hypothesis that MBNL2 depletion leads to behavioral sensitivity to GABAA-R modulation, Mbnl2 KO and WT littermates were treated with the anesthetic sevoflurane, the benzodiazepine diazepam, the imidazopyridine zolpidem, and the benzodiazepine rescue agent, flumazenil (Ro 15-1788), and assessed for various behavioral metrics. Mbnl2 KO mice exhibited delayed recovery following sevoflurane, delayed emergence and recovery from zolpidem, and enhanced sleep time at baseline that was modulated by flumazenil (Ro 15-1788). A significantly higher proportion of Mbnl2 KO mice also loss their righting reflex (LORR) from a standard d...

Low-frequency (<200 Hz), subperception spinal cord stimulation (SCS) is a novel modality demonstrating therapeutic efficacy for treating chronic neuropathic pain. When stimulation parameters were carefully titrated, patients experienced rapid onset (seconds – minutes) pain relief without paresthesia, but the mechanisms of action are unknown. Using an integrated computational model and in vivo measurements in urethane-anesthetized rats, we quantified how stimulation parameters (placement, pulse width, frequency, and amplitude) influenced dorsal column (DC) axon activation and neural responses in the dorsal horn (DH). Both modeled and recorded DC axons responded with irregular spiking patterns in response to low-amplitude SCS. Maximum inhibition of DH neurons occurred at ∼80% of the predicted sensory threshold in both modeled and recorded neurons, and responses were strongly dependent on spatially targeting of stimulation, i.e., the complement of DC axons activated, and on stimulation parameters. Intrathecal...

Temporal nesting of cortical slow oscillations, thalamic spindles, and hippocampal ripples indicates multiregional neuronal interactions required for memory consolidation. However, how the thalamic activity during spindles organizes hippocampal dynamics remains largely undetermined. We analyzed simultaneous recordings of anterodorsal thalamus and CA1 in male mice to determine the contribution of thalamic spindles in cross-regional synchronization. Our results indicated that temporal hippocampo-thalamocortical coupling was more enhanced during slower and longer thalamic spindles. Additionally, spindles occurring closer to slow oscillation trough were more strongly coupled to ripples. We found that the temporal association between CA1 spiking/ripples and thalamic spindles was stronger following spatial exploration compared with baseline sleep. We further developed a hippocampal-thalamocortical model to explain the mechanism underlying the duration and frequency-dependent coupling of thalamic spindles to hipp...

The NMDARs are key players in both physiological and pathologic synaptic plasticity because of their involvement in many aspects of neuronal transmission as well as learning and memory. The contribution in these events of different types of GluN2A-interacting proteins is still unclear. The p140Cap scaffold protein acts as a hub for postsynaptic complexes relevant to psychiatric and neurologic disorders and regulates synaptic functions, such as the stabilization of mature dendritic spine, memory consolidation, LTP, and LTD. Here we demonstrate that p140Cap directly binds the GluN2A subunit of NMDAR and modulates GluN2A-associated molecular network. Indeed, in p140Cap KO male mice, GluN2A is less associated with PSD95 both in ex vivo synaptosomes and in cultured hippocampal neurons, and p140Cap expression in KO neurons can rescue GluN2A and PSD95 colocalization. p140Cap is crucial in the recruitment of GluN2A-containing NMDARs and, consequently, in regulating NMDARs' intrinsic properties. p140Cap is associat...