Hippocampal seizures are a defining feature of mesial temporal lobe epilepsy. Area CA1 of the hippocampus is commonly implicated in the generation of seizures, which may occur due to 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 in mice enabled by a transparent graphene-based microelectrode array. We examine pyramidal cell 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 seizures. Signi...

Endosomal transport and positioning cooperate in the establishment of neuronal compartment architecture, dynamics and function, contributing to neuronal intracellular logistics. Furthermore, dysfunction of endo-lysosomal has been identified as a common mechanism in neurodegenerative diseases. Here, we analyzed endo-lysosomal transport when α-synuclein (α-syn) fibrillar polymorphs, ß-amyloid (Aß) fibrils and oligomers were externally applied on primary cultures of mouse cortical neurons. To measure this transport, we used a simple readout based on the spontaneous endocytosis in cultured neurons of fluorescent nanodiamonds, a perfectly stable nano-emitter, and the subsequent automatic extraction and quantification of their directed motions at high-throughput. α-syn fibrillar polymorphs, Aß fibrils and oligomers induce a two-fold decrease of the fraction of nanodiamonds transported along microtubules, while only slightly reducing their interaction with cortical neurons. This important decrease in moving endos...

Sensing the movement of fast objects within our visual environments is essential for controlling actions. It requires online estimation of motion direction and speed. We probed human speed representation using ocular tracking of stimuli of different statistics. First, we compared ocular responses to single drifting gratings with a given set of spatiotemporal frequencies to broadband Motion Clouds of matched mean frequencies. Motion energy distributions of gratings and clouds are point-like, and ellipses oriented along the constant speed axis, respectively. Sampling frequency space, Motion Clouds elicited stronger, less variable and speed-tuned responses. Drifting gratings yielded weaker and more frequency-tuned responses. Second, we measured responses to patterns made of two or three components covering a range of orientations within Fourier space. Early tracking initiation of the patterns was best predicted by a linear combination of components before nonlinear interactions emerged to shape later dynamics...

The neural underpinnings of humans’ ability to process faces and how it changes over typical development have been extensively studied using paradigms where face stimuli are oversimplified, isolated, and de-contextualized. The prevalence of this approach, however, has resulted in limited knowledge of face processing in ecologically valid situations, in which faces are accompanied by contextual information at multiple time scales. In the present study, we use a naturalistic movie paradigm to investigate how neuromagnetic activation and phase synchronization elicited by faces from movie scenes in humans differ between children and adults. We used MEG data from 22 adults (6 females, 3 left-handed, mean age 27.7±5.28 years old) and 20 children (7 females, 1 left-handed, mean age 9.5±1.52 years old) collected during movie viewing. We investigated neuromagnetic time-locked activation and phase synchronization elicited by movie scenes containing faces. Statistical differences between groups were tested using a mu...

The presynaptic action potential (AP) is required to drive calcium influx into nerve terminals, resulting in neurotransmitter release. Accordingly, the AP waveform is crucial in determining the timing and strength of synaptic transmission. The calyx of Held nerve terminals of rats of either sex showed minimum changes in AP waveform during high-frequency AP firing. We found that the stability of the calyceal AP waveform requires KCNQ (KV7) K+ channel activation during high-frequency spiking activity. High-frequency presynaptic spikes gradually led to accumulation of KCNQ channels in open states which kept interspike membrane potential sufficiently negative to maintain Na+ channel availability. Blocking KCNQ channels during stimulus trains led to inactivation of presynaptic Na+, and to a lesser extent KV1 channels, thereby reducing the AP amplitude and broadening AP duration. Moreover, blocking KCNQ channels disrupted the stable calcium influx and glutamate release required for reliable synaptic transmission...

Feedforward and feedback pathways interact in specific dendritic domains to enable cognitive functions such as predictive processing and learning. Based on axonal projections, hierarchically lower areas are thought to form synapses primarily on dendrites in middle cortical layers, whereas higher-order areas are thought to target dendrites in layer 1 and in deep layers. However, the extent to which functional synapses form in regions of axodendritic overlap has not been extensively studied. Here, we use viral tracing in the secondary visual cortex of male mice to map brain-wide inputs to thick-tufted layer 5 pyramidal neurons. Furthermore, we provide a comprehensive map of input locations through subcellular optogenetic circuit mapping. We show that input pathways target distinct dendritic domains with far greater specificity than appears from their axonal branching, often deviating substantially from the canonical patterns. Common assumptions regarding the dendrite-level interaction of feedforward and feed...

Aging is associated with a bias in attention and memories toward positive and away from negative emotional content. In addition, emotion regulation appears to improve with age, despite concomitant widespread cognitive decline coupled with gray matter volume loss in cortical and subcortical regions thought to subserve emotion regulation. Here, we address this emotion-aging paradox using the behavioral data of an emotion regulation task from a population-derived, male and female, human sample (CamCAN) and use structural equation modeling together with multivariate analysis of structural MRI images of the same sample to investigate brain–behavior relationships. In a series of measurement models, we show the relationship between age and emotionality is best explained by a four-factor model, compared with single and hierarchical factor models. These four latent factors are interpreted as Basal Negative Affect, Positive Reactivity, Negative Reactivity and Positive Regulation (upregulating positive emotion to neg...

Several cellular pathways contribute to neurodegenerative tauopathy-related disorders. Microglial activation, a major component of neuroinflammation, is an early pathologic hallmark that correlates with cognitive decline, while the unfolded protein response (UPR) contributes to synaptic pathology. Sleep disturbances are prevalent in tauopathies and may also contribute to disease progression. Few studies have investigated whether manipulations of sleep influence cellular pathologic and behavioral features of tauopathy. We investigated whether trazodone, a licensed antidepressant with hypnotic efficacy in dementia, can reduce disease-related cellular pathways and improve memory and sleep in male rTg4510 mice with a tauopathy-like phenotype. In a 9 week dosing regimen, trazodone decreased microglial NLRP3 inflammasome expression and phosphorylated p38 mitogen-activated protein kinase levels, which correlated with the NLRP3 inflammasome, the UPR effector ATF4, and total tau levels. Trazodone reduced theta osci...

Decisions to act while pursuing goals in the presence of danger must be made quickly but safely. Premature decisions risk injury or death, whereas postponing decisions risk goal loss. Here we show how mice resolve these competing demands. Using microstructural behavioral analyses, we identified the spatiotemporal dynamics of approach–avoidance decisions under motivational conflict in male mice. Then we used cognitive modeling to show that these dynamics reflect the speeded decision-making mechanisms used by humans and nonhuman primates, with mice trading off decision speed for safety of choice when danger loomed. Using calcium imaging in paraventricular thalamus and optogenetic inhibition of the prelimbic cortex to paraventricular thalamus pathway, we show that this speed-safety trade off occurs because increases in paraventricular thalamus activity increase decision caution, thereby increasing approach–avoid decision times in the presence of danger. Our findings demonstrate that a discrete brain circuit i...