Hippocampal seizures are a defining feature of mesial temporal lobe epilepsy (MTLE). Area CA1 of the hippocampus is commonly implicated in the generation of seizures, which may occur because of the activity of endogenous cell populations or of inputs from other regions within the hippocampal formation. Simultaneously observing activity at the cellular and network scales in vivo remains challenging. Here, we present a novel technology for simultaneous electrophysiology and multicellular calcium imaging of CA1 pyramidal cells (PCs) in mice enabled by a transparent graphene-based microelectrode array (Gr MEA). We examine PC firing at seizure onset, oscillatory coupling, and the dynamics of the seizure traveling wave as seizures evolve. Finally, we couple features derived from both modalities to predict the speed of the traveling wave using bootstrap aggregated regression trees. Analysis of the most important features in the regression trees suggests a transition among states in the evolution of hippocampal se...

A topographic map of auditory space is a feature found in the superior colliculus (SC) of many species, including CBA/CaJ mice. In this genetic background, high-frequency monaural spectral cues and interaural level differences (ILDs) are used to compute spatial receptive fields (RFs) that form a topographic map along the azimuth. Unfortunately, C57BL/6 mice, a strain widely used for transgenic manipulation, display age-related hearing loss (AHL) because of an inbred mutation in the Cadherin 23 gene ( Cdh23 ) that affects hair cell mechanotransduction. To overcome this problem, researchers have used young C57BL/6 mice in their studies, as they have been shown to have normal hearing thresholds. However, important details of the auditory response characteristics of the SC such as spectral responses and spatial localization, have not been characterized in young C57BL/6 mice. Here, we show that two- to four-month C57BL/6 mice lack neurons with frontal auditory RFs and therefore lack a topographic representation...

The generation of surrogate data, i.e., the modification of data to destroy a certain feature, can be considered as the implementation of a null-hypothesis whenever an analytical approach is not feasible. Thus, surrogate data generation has been extensively used to assess the significance of spike correlations in parallel spike trains. In this context, one of the main challenges is to properly construct the desired null-hypothesis distribution and to avoid altering the single spike train statistics. A classical surrogate technique is uniform dithering (UD), which displaces spikes locally and uniformly distributed, to destroy temporal properties on a fine timescale while keeping them on a coarser one. Here, we compare UD against five similar surrogate techniques in the context of the detection of significant spatiotemporal spike patterns. We evaluate the surrogates for their performance, first on spike trains based on point process models with constant firing rate, and second on modeled nonstationary artifi...

The migration of neurons from their birthplace to their correct destination is one of the most crucial steps in brain development. Incomplete or incorrect migration yields ectopic neurons, which cause neurologic deficits or are negligible at best. However, the granule cells (GCs) in the cerebellar cortex may challenge this traditional view of ectopic neurons. When animals are born, GCs proliferate near the pia mater and then migrate down to the GC layer located deep in the cerebellar cortex. However, some GC-like cells stay in the molecular layer, a layer between the pia mater and GC layer, even in normal adult animals. These cells were named ectopic GCs nearly 50 years ago, but their abundance and functional properties remain unclear. Here, we have examined GCs in the molecular layer (mGCs) with a specific marker for mature GCs and transgenic mice in which GCs are sparsely labeled with a fluorescent protein. Contrary to the previous assumption that mGCs are a minor neuronal population, we have found that ...

Actions have consequences. Motor learning involves correcting actions that lead to movement errors and remembering these actions for future behavior. In most laboratory situations, movement errors have no physical consequences and simply indicate the progress of learning. Here, we asked how experiencing a physical consequence when making a movement error affects motor learning. Two groups of participants adapted to a new, prism-induced mapping between visual input and motor output while performing a precision walking task. Importantly, one group experienced an unexpected slip perturbation when making foot-placement errors during adaptation. Because of our innate drive for safety, and the fact that balance is fundamental to movement, we hypothesized that this experience would enhance motor memory. Learning generalized to different walking tasks to a greater extent in the group who experienced the adverse physical consequence. This group also showed faster relearning one week later despite exposure to a comp...

Aging leads to degeneration of the peripheral and central auditory systems, hearing loss, and difficulty understanding sounds in noise. Aging is also associated with changes in susceptibility to or recovery from damaging noise exposures, although the effects of the interaction between acute noise exposure and age on the perception of sounds are not well studied. We tested these effects in the CBA/CaJ mouse model of age-related hearing loss using operant conditioning procedures before and after noise exposure and longitudinally measured changes in their sensitivity for detecting tones in quiet or noise backgrounds. Cochleae from a subset of the behaviorally tested mice were immunolabeled to examine organ of Corti damage relative to what is expected based on aging alone. Mice tested in both quiet and noise background conditions experienced worse behavioral sensitivity immediately after noise exposure, but mice exposed at older ages generally showed greater threshold shifts and reduced recovery over time. Sur...

The endogenous opioid system plays a crucial role in stress-induced analgesia. Mu-opioid receptors (MORs), one of the major opioid receptors, are expressed widely in subpopulations of cells throughout the CNS. However, the potential roles of MORs expressed in glutamatergic (MORGlut) and γ-aminobutyric acidergic (MORGABA) neurons in stress-induced analgesia remain unclear. By examining tail-flick latencies to noxious radiant heat of male mice, here we investigated the contributions of MORGABA and MORGlut to behavioral analgesia and activities of neurons projecting from periaqueductal gray (PAG) to rostral ventromedial medulla (RVM) induced by a range of time courses of forced swim exposure. The moderate but not transitory or prolonged swim exposure induced a MOR-dependent analgesia, although all of these three stresses enhanced β-endorphin release. Selective deletion of MORGABA but not MORGlut clearly attenuated analgesia and blocked the enhancement of activities of PAG-RVM neurons induced by moderate swim ...

Among the modulatory functions of thyrotropin-releasing hormone (TRH), an anorectic behavior in rodents is observed when centrally injected. Hypothalamic paraventricular nucleus (PVN) neurons receive serotonergic inputs from dorsal raphe nucleus and express serotonin (5HT) receptors such as 5HT1A, 5HT2A/2C, 5HT6, which are involved in 5HT-induced feeding regulation. Rats subjected to dehydration-induced anorexia (DIA) model show increased PVN TRH mRNA expression, associated with their decreased food intake. We analyzed whether 5HT input is implicated in the enhanced PVN TRH transcription that anorectic rats exhibit, given that 5HT increases TRH expression and release when studied in vitro . By using mHypoA-2/30 hypothalamic cell cultures, we found that 5HT stimulated TRH mRNA, pCREB, and pERK1/2 levels. By inhibiting basal PKA or PKC activities or those induced by 5HT, pCREB or pERK1/2 content did not increase suggesting involvement of both kinases in their phosphorylation. 5HT effect on TRH mRNA was not a...

Type 3 vesicular glutamate transporter (VGLUT3) represents a unique modulator of glutamate release from both nonglutamatergic and glutamatergic varicosities within the brain. Despite its limited abundance, VGLUT3 is vital for the regulation of glutamate signaling and, therefore, modulates the activity of various brain microcircuits. However, little is known about how glutamate receptors are regulated by VGLUT3 across different brain regions. Here, we used VGLUT3 constitutive knock-out (VGLUT3–/–) mice and explored how VGLUT3 deletion influences total and cell surface expression of different ionotropic and metabotropic glutamate receptors. VGLUT3 deletion upregulated the overall expression of metabotropic glutamate receptors mGluR5 and mGluR2/3 in the cerebral cortex. In contrast, no change in the total expression of ionotropic NMDAR glutamate receptors were observed in the cerebral cortex of VGLUT3–/– mice. We noted significant reduction in cell surface levels of mGluR5, NMDAR2A, NMDAR2B, as well as reduct...

Activity-dependent modifications of synaptic efficacies are a cellular substrate of learning and memory. Experimental evidence shows that these modifications are synapse specific and that the long-lasting effects are associated with the sustained increase in concentration of specific proteins like PKM ζ . However, such proteins are likely to diffuse away from their initial synaptic location and spread out to neighboring synapses, potentially compromising synapse specificity. In this article, we address the issue of synapse specificity during memory maintenance. Assuming that the long-term maintenance of synaptic plasticity is accomplished by a molecular switch, we carry out analytical calculations and perform simulations using the reaction-diffusion package in NEURON to determine the limits of synapse specificity during maintenance. Moreover, we explore the effects of the diffusion and degradation rates of proteins and of the geometrical characteristics of dendritic spines on synapse specificity. We conclu...