The voltage-gated calcium channel subunit α2δ-2 controls calcium-dependent signaling in neurons, and loss of this subunit causes epilepsy in both mice and humans. To determine whether mice without α2δ-2 demonstrate hippocampal activation or histopathological changes associated with seizure activity, we measured expression of the activity-dependent gene c -fos and various histopathological correlates of temporal lobe epilepsy (TLE) in hippocampal tissue from wild-type (WT) and α2δ-2 knock-out ( CACNA2D2 KO) mice using immunohistochemical staining and confocal microscopy. Both genotypes demonstrated similarly sparse c- fos and ΔFosB expressions within the hippocampal dentate granule cell layer (GCL) at baseline, consistent with no difference in basal activity of granule cells between genotypes. Surprisingly, when mice were assayed 1 h after handling-associated convulsions, KO mice had fewer c- fos -positive cells but dramatically increased ΔFosB expression in the dentate gyrus compared with WT mice. After ad...

The ability to remember changes in the surroundings is fundamental for daily life. It has been proposed that novel events producing dopamine release in the hippocampal CA1 region could modulate spatial memory formation. However, the role of hippocampal dopamine increase on weak or strong spatial memories remains unclear. We show that male mice exploring two objects located in a familiar environment for 5 min created a short-term memory (weak) that cannot be retrieved 1 d later, whereas 10 min exploration created a long-term memory (strong) that can be retrieved 1 d later. Remarkably, hippocampal dopamine elevation during the encoding of weak object location memories (OLMs) allowed their retrieval 1 d later but dopamine elevation during the encoding of strong OLMs promoted the preference for a familiar object location over a novel object location after 24 h. Moreover, dopamine uncaging after the encoding of OLMs did not have effect on weak memories whereas on strong memories diminished the exploration of th...

Elicited upon violation of regularity in stimulus presentation, mismatch negativity (MMN) reflects the brain's ability to perform automatic comparisons between consecutive stimuli and provides an electrophysiological index of sensory error detection whereas P300 is associated with cognitive processes such as updating of the working memory. To date, there has been extensive research on the roles of MMN and P300 individually, because of their potential to be used as clinical markers of consciousness and attention, respectively. Here, we intend to explore with an unsupervised and rigorous source estimation approach, the underlying cortical generators of MMN and P300, in the context of prediction error propagation along the hierarchies of brain information processing in healthy human participants. The existing methods of characterizing the two ERPs involve only approximate estimations of their amplitudes and latencies based on specific sensors of interest. Our objective is twofold: first, we introduce a novel ...

The corpus callosum is composed of several subregions, distinct in cellular and functional organization. This organization scheme may render these subregions differentially vulnerable to the aging process. Callosal integrity may be further compromised by cardiovascular risk factors, which negatively influence white matter health. Here, we test for heterochronicity of aging, hypothesizing an anteroposterior gradient of vulnerability to aging that may be altered by the effects of cardiovascular health. In 174 healthy adults across the adult lifespan (mean age = 53.56 ± 18.90; range, 20–94 years old, 58.62% women), pulse pressure (calculated as participant's systolic minus diastolic blood pressure) was assessed to determine cardiovascular risk. A deterministic tractography approach via diffusion-weighted imaging was utilized to extract fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) from each of five callosal subregions, serving as estimates of microstructural health. General l...

Mismatch negativity (MMN) is commonly recognized as a neural signal of prediction error evoked by deviants from the expected patterns of sensory input. Studies show that MMN diminishes when sequence patterns become more predictable over a longer timescale. This implies that MMN is composed of multiple subcomponents, each responding to different levels of temporal regularities. To probe the hypothesized subcomponents in MMN, we record human electroencephalography during an auditory local–global oddball paradigm where the tone-to-tone transition probability (local regularity) and the overall sequence probability (global regularity) are manipulated to control temporal predictabilities at two hierarchical levels. We find that the size of MMN is correlated with both probabilities and the spatiotemporal structure of MMN can be decomposed into two distinct subcomponents. Both subcomponents appear as negative waveforms, with one peaking early in the central-frontal area and the other late in a more frontal area. W...

Why does groundbreaking progress in our understanding of the brain seem scarce (at least to me)? The prevailing system of research funding and publication, deeply rooted in peer review and contingent upon preliminary data, tends to favor safe, conventional ideas, thereby impeding major breakthroughs. The prerequisite of preliminary data for hypothesis validation transforms grant-seeking into a cycle that prioritizes data accumulation over pioneering ideas, fostering publications that align with pre-established notions endorsed by reviewers. Are we, the scientists, becoming akin to the subjects of our experiments? Consider this: in behavioral studies, rodents are often deprived of food and water to motivate their learning of a task. Since a successful task is rewarded, animals quickly learn the task and become very efficient at it after some time. Now, envision neuroscientists in a similar plight, navigating the pursuit of funding and recognition in high-profile journals. This predicament is faced by many (...

In the article, “Context Binding in Visual Working Memory Is Reflected in Bilateral Event-Related Potentials, But Not in Contralateral Delay Activity,” by Ying Cai, Jacqueline M. Fulvio, Jason Samaha, …

Infrared neural stimulation (INS) is a promising area of interest for the clinical application of a neuromodulation method. This is in part because of its low invasiveness, whereby INS modulates the activity of neural tissue mainly through temperature changes. Additionally, INS may provide localized brain stimulation with less tissue damage. The inferior colliculus (IC) is a crucial auditory relay nuclei, and a potential target for clinical application of INS to treat auditory diseases and develop artificial hearing devices. Here, using continuous INS with low to high power density, we demonstrate laminar modulation of neural activity in the mouse IC in the presence and absence of sound. We investigated stimulation parameters of INS to effectively modulate neural activity in a facilitatory or inhibitory manner. A mathematical model of INS-driven brain tissue was first simulated, temperature distributions were numerically estimated, and stimulus parameters were selected from the simulation results. Subseque...

Autism spectrum disorder (ASD) is often associated with social communication impairments and specific sound processing deficits, for example, problems in following speech in noisy environments. To investigate underlying neuronal processing defects located in the auditory cortex (AC), we performed two-photon Ca2+ imaging in FMR1 ( fragile X messenger ribonucleoprotein 1 ) knock-out (KO) mice, a model for fragile X syndrome (FXS), the most common cause of hereditary ASD in humans. For primary AC (A1) and the anterior auditory field (AAF), topographic frequency representation was less ordered compared with control animals. We additionally analyzed ensemble AC activity in response to various sounds and found subfield-specific differences. In A1, ensemble correlations were lower in general, while in secondary AC (A2), correlations were higher in response to complex sounds, but not to pure tones. Furthermore, sound specificity of ensemble activity was decreased in AAF. Repeating these experiments 1 week later re...

Canonically, action potentials of most mammalian neurons initiate at the axon initial segment (AIS) and propagate bidirectionally: orthodromically along the distal axon and retrogradely into the soma and dendrites. Under some circumstances, action potentials may initiate ectopically, at sites distal to the AIS, and propagate antidromically along the axon. These “ectopic action potentials” (EAPs) have been observed in experimental models of seizures and chronic pain, and more rarely in nonpathological forebrain neurons. Here we report that a large majority of parvalbumin-expressing (PV+) interneurons in the upper layers of mouse neocortex, from both orbitofrontal and primary somatosensory areas, fire EAPs after sufficient activation of their somata. Somatostatin-expressing interneurons also fire EAPs, though less robustly. Ectopic firing in PV+ cells occurs in varying temporal patterns and can persist for several seconds. PV+ cells evoke strong synaptic inhibition in pyramidal neurons and interneurons and p...