GABAergic somatodendritic inhibition in the preBötzinger complex (preBötC), a medullary site for the generation of inspiratory rhythm, is involved in respiratory rhythmogenesis and patterning. Nevertheless, whether GABA acts distally on presynaptic terminals, evoking presynaptic inhibition is unknown. Here, we begin to address this problem by measuring presynaptic Ca2+ transients in preBötC neurons, under rhythmic and non-rhythmic conditions, with two variants of genetically encoded Ca2+ indicators (GECIs). Organotypic slice cultures from newborn mice, containing the preBötC, were drop-transduced with jGCaMP7s, or injected with jGCaMP7f-labeling commissural preBötC neurons. Then, Ca2+ imaging combined with whole-cell patch-clamp or field stimulation was obtained from inspiratory preBötC neurons. We found that rhythmically active neurons expressed synchronized Ca2+ transients in soma, proximal and distal dendritic regions, and punctate synapse-like structures. Expansion microscopy revealed morphologic chara...

Full-band DC recordings enable recording of slow electrical brain signals that are severely compromised during conventional AC recordings. However, full-band DC recordings may be limited by the amplifier’s dynamic input range and the loss of small amplitude high-frequency signals. Recently, Neuralynx has proposed full-band recordings with inverse filtering for signal reconstruction based on hybrid AC/DC-divider RRC filters that enable only partial suppression of DC signals. However, the quality of signal reconstruction for biological signals has not yet been assessed. Here, we propose a novel digital inverse filter based on a mathematical model describing RRC filter properties, which provides high computational accuracy and versatility. Second, we propose procedures for the evaluation of the inverse filter coefficients, adapted for each recording channel to minimize the error caused by the deviation of the real values of the RRC filter elements from their nominal values. We demonstrate that this approach e...

When listening to speech, low-frequency cortical activity tracks the speech envelope. It remains controversial, however, whether such envelope-tracking neural activity reflects entrainment of neural oscillations or superposition of transient responses evoked by sound features. Recently, it is suggested that the phase of envelope-tracking activity can potentially distinguish entrained oscillations and evoked responses. Here, we analyze the phase of envelope-tracking in humans during passive listening, and observe that the phase lag between cortical activity and speech envelope tends to change linearly across frequency in the θ band (4–8 Hz), suggesting that the θ-band envelope-tracking activity can be readily modeled by evoked responses.

Mammalian orienting behavior consists of coordinated movements of the eyes, head, pinnae, vibrissae, or body to attend to an external stimulus. The present study aimed to develop a novel operant task using a touch-screen system to measure spatial attention. In this task, rats were trained to nose-poke a light stimulus presented in one of three locations. The stimulus was presented more frequently in the center location to develop spatial attention bias toward the center stimulus. Changes in orienting responses were detected by measuring the animals’ response accuracy and latency to stimuli at the lateral locations, following reversible unilateral chemogenetic inactivation of the superior colliculus (SC). Additionally, spontaneous turning and rotation behavior was measured using an open-field test (OFT). Our results show that right SC inactivation significantly increased the whole body turn angle in the OFT, in line with previous literature that indicated an ipsiversive orientating bias and the presence of ...

Generalization of sensorimotor adaptation across limbs, known as interlimb transfer, is a well-demonstrated phenomenon in humans, yet the underlying neural mechanisms remain unclear. Theoretical models suggest that interlimb transfer is mediated by interhemispheric transfer of information via the corpus callosum. We thus hypothesized that lesions of the corpus callosum, especially to its midbody connecting motor, supplementary motor, and premotor areas of the two cerebral hemispheres, would impair interlimb transfer of sensorimotor adaptation. To test this hypothesis, we recruited three patients: two rare stroke patients with recent, extensive callosal lesions including the midbody and one patient with complete agenesis. A prismatic adaptation paradigm involving unconstrained arm reaching movements was designed to assess interlimb transfer from the prism-exposed dominant arm (DA) to the unexposed non-dominant arm (NDA) for each participant. Baseline results showed that spatial performance of each patient d...

The inflexible repetitive behaviors and “insistence on sameness” seen in autism imply a defect in neural processes controlling the balance between stability and plasticity of synaptic connections in the brain. It has been proposed that abnormalities in the Ras-ERK/MAPK pathway, a key plasticity-related cell signaling pathway known to drive consolidation of clustered synaptic connections, underlie altered learning phenotypes in autism. However, a link between altered Ras-ERK signaling and clustered dendritic spine plasticity has yet to be explored in an autism animal model in vivo . The formation and stabilization of dendritic spine clusters is abnormally increased in the MECP2-duplication syndrome mouse model of syndromic autism, suggesting that ERK signaling may be increased. Here, we show that the Ras-ERK pathway is indeed hyperactive following motor training in MECP2-duplication mouse motor cortex. Pharmacological inhibition of ERK signaling normalizes the excessive clustered spine stabilization and enh...

The orbitofrontal cortex (OFC) is a brain region involved in higher-order decision-making. Rodent studies show that cocaine self-administration (CSA) reduces OFC contribution to goal-directed behavior and behavioral strategies to avoid drug intake. This change in OFC function persists for many weeks after cocaine withdrawal, suggesting involvement in the process of addiction. The mechanisms underlying impaired OFC function by cocaine are not well-understood. However, studies implicate altered OFC serotonin (5-HT) function in disrupted cognitive processes during addiction and other psychiatric disorders. Thus, it is hypothesized that cocaine impairment of OFC function involves changes in 5-HT signaling, and previous work shows that 5-HT1A and 5-HT2A receptor-mediated effects on OFC pyramidal neurons (PyNs) are impaired weeks after cocaine withdrawal. However, 5-HT effects on other contributors to OFC circuit function have not been fully investigated, including the parvalbumin-containing, fast-spiking intern...

New information is rarely learned in isolation; instead, most of what we experience can be incorporated into or uses previous knowledge networks in some form. Previous knowledge in form of a cognitive map can facilitate knowledge acquisition and will influence how we learn new spatial information. Here, we developed a new spatial navigation task where food locations are learned in a large, gangway maze to test how mice learn a large spatial map over a longer time period—the HexMaze. Analyzing performance across sessions as well as on specific trials, we can show simple memory effects as well as multiple effects of previous knowledge of the map accelerating both online learning and performance increases over offline periods when incorporating new information. We could identify the following three main phases: (1) learning the initial goal location; (2) faster learning after 2 weeks when learning a new goal location; and then (3) the ability to express one-session learning, leading to long-term memory effect...

Intercellular adhesion molecule-1 (ICAM-1) promotes adhesion and transmigration of circulating leukocytes across the blood-brain barrier (BBB). Traumatic brain injury (TBI) causes transmigrated immunocompetent cells to release mediators [function-associated antigen (LFA)-1 and macrophage-1 antigen (Mac-1)] that stimulate glial and endothelial cells to express ICAM-1 and release cytokines, sustaining neuroinflammation and neurodegeneration. Although a strong correlation exists between TBI-mediated inflammation and impairment in functional outcome following brain trauma, the role of ICAM-1 in impairing functional outcome by inducing neuroinflammation and neurodegeneration after TBI remains inconclusive. The experimental TBI was induced in vivo by fluid percussion injury (FPI; 10 and 20 psi) in wild-type (WT) and ICAM-1 −/− mice and in vitro by stretch injury (3 psi) in brain endothelial cells. We manipulate ICAM-1 pharmacologically and genetically and conducted several biochemical analyses to gain insight in...

Dopamine replacement by levodopa (L-DOPA) is the most widely used therapy for Parkinson’s disease (PD), however patients often develop side effects, known as L-DOPA-induced dyskinesia (LID), that usually need therapeutic intervention. There are no suitable therapeutic options for LID, except for the use of the NMDA receptor (NMDA-R) antagonist amantadine, which has limited efficacy. The NMDA-R is indeed the most plausible target to manage LID in PD and recently the kinase Fyn, one of its key regulators, became a new putative molecular target involved in LID. The aim of this work was to reduce Fyn expression to alleviate LID in a mouse model of PD. We performed intrastriatal delivery of a designed micro-RNA against Fyn (miRNA-Fyn) in 6-OHDA-lesioned mice treated with L-DOPA. The miRNA-Fyn was delivered either before or after L-DOPA exposure to assess its ability to prevent or revert dyskinesia. Preadministration of miRNA-Fyn reduced LID with a concomitant reduction of FosB-ΔFosB protein levels, a marker of ...