Sleep and sleep loss are thought to impact synaptic plasticity, and recent studies have shown that sleep and sleep deprivation (SD) differentially affect gene transcription and protein translation in the mammalian forebrain. However, much less is known regarding how sleep and SD affect these processes in different microcircuit elements within the hippocampus and neocortex - for example, in inhibitory vs. excitatory neurons. Here we use translating ribosome affinity purification (TRAP) and in situ hybridization to characterize the effects of sleep vs. SD on abundance of ribosome-associated transcripts in Camk2a-expressing (Camk2a+) pyramidal neurons and parvalbumin-expressing (PV+) interneurons in the hippocampus and neocortex of male mice. We find that while both Camk2a+ neurons and PV+ interneurons in neocortex show concurrent SD-driven increases in ribosome-associated transcripts for activity-regulated effectors of plasticity and transcriptional regulation, these transcripts are minimally affected by SD ...

Signal correlation ( r s) is commonly defined as the correlation between the tuning curves of two neurons and is widely used as a metric of tuning similarity. It is fundamental to how populations of neurons represent stimuli and has been central to many studies of neural coding. Yet the classic estimate, Pearson’s correlation coefficient, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline"><mml:mrow><mml:msub><mml:mover accent="true"><mml:mi>r</mml:mi><mml:mo>^</mml:mo></mml:mover><mml:mi mathvariant="normal">s</mml:mi></mml:msub></mml:mrow></mml:math> , between the average responses of two neurons to a set of stimuli suffers from confounding biases. The estimate <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline"><mml:mrow><mml:msub><mml:mover accent="true"><mml:mi>r</mml:mi><mml:mo>^</mml:mo></mml:mover><mml:mi mathvariant="normal">s</mml:mi></mml:msub></mml:mrow></mml:math> can be downwardly biased by trial-to-trial variability and also upwardly biased by tri...

The substantia nigra pars reticulata (SNr) is the output station of the basal ganglia and receives cortical inputs by way of three basal ganglia pathways: the cortico-subthalamo (STN)-SNr hyperdirect, cortico-striato-SNr direct, and cortico-striato-external pallido-STN-SNr indirect pathways. Compared to the classical direct and indirect pathways via the striatum, the functions of the hyperdirect pathway remain to be fully elucidated. Here we used a photodynamic technique to selectively eliminate the cortico-STN projection in male mice and observed neuronal activity and motor behaviors in awake conditions. After cortico-STN elimination, cortically evoked early excitation in the SNr was diminished, while the cortically evoked inhibition and late excitation, which are delivered through the direct and indirect pathways, respectively, were unchanged. In addition, locomotor activity was significantly increased after bilateral cortico-STN elimination, and apomorphine-induced ipsilateral rotations were observed af...

Rapid sensory adaptation is observed across all sensory systems, and strongly shapes sensory percepts in complex sensory environments. Yet despite its ubiquity and likely necessity for survival, the mechanistic basis is poorly understood. A wide range of primarily in-vitro and anesthetized studies have demonstrated the emergence of adaptation at the level of primary sensory cortex, with only modest signatures in earlier stages of processing. The nature of rapid adaptation and how it shapes sensory representations during wakefulness, and thus the potential role in perceptual adaptation, is underexplored, as are the mechanisms that underlie this phenomenon. To address these knowledge gaps, we recorded spiking activity in primary somatosensory cortex (S1) and the upstream ventral posteromedial (VPm) thalamic nucleus in the vibrissa pathway of awake male and female mice, and quantified responses to whisker stimuli delivered in isolation and embedded in an adapting sensory background. We found that cortical sen...

Impairment of episodic memory, a class of memory for spatiotemporal context of an event, is an early symptom of Alzheimer’s disease. Both spatial and temporal information are encoded and represented in the hippocampal neurons, but how these representations are impaired under amyloid β (Aβ) pathology remains elusive. We performed chronic imaging of the hippocampus in awake male amyloid precursor protein ( App ) knock-in mice behaving in a virtual reality environment to simultaneously monitor spatiotemporal representations and the progression of Aβ depositions. We found that temporal representation is preserved, while spatial representation is significantly impaired in the App knock-in mice. This is due to the overall reduction of active place cells but not time cells, and compensatory hyperactivation of remaining place cells near Aβ aggregates. These results indicate the differential impact of Aβ aggregates on two major modalities of episodic memory, suggesting different mechanisms for forming and maintaini...

A visual object is characterized by multiple visual features, including its identity, position and size. Despite the usefulness of identity and nonidentity features in vision and their joint coding throughout the primate ventral visual processing pathway, they have so far been studied relatively independently. Here in both female and male human participants, the coding of identity and nonidentity features was examined together across the human ventral visual pathway. The nonidentity features tested included two Euclidean features (position and size) and two non-Euclidean features (image statistics and spatial frequency (SF) content of an image). Overall, identity representation increased and nonidentity feature representation decreased along the ventral visual pathway, with identity outweighing the non-Euclidean but not the Euclidean features at higher levels of visual processing. In 14 convolutional neural networks (CNNs) pretrained for object categorization with varying architecture, depth, and with/with...

Tau aggregation within neurons is a critical feature of Alzheimer's disease (AD) and related tauopathies. It is believed that soluble pathologic tau species seed the formation of tau aggregates in a prion-like manner and propagate through connected neurons during the progression of disease. Both soluble and aggregated forms of tau are thought to have neurotoxic properties. In addition, different strains of misfolded tau may cause differential neurotoxicity. In this work, we present an accelerated human neuronal model of tau-induced neurotoxicity that incorporates both soluble tau species and tau aggregation. Using patient-derived induced pluripotent stem cell (iPSC) neurons expressing a tau aggregation biosensor, we develop a cell culture system that allows continuous assessment of both induced tau aggregation and neuronal viability at single-cell resolution for periods of >1 week. We show that exogenous tau “seed” uptake, as measured by tau repeat domain (TauRD) reporter aggregation, increases the risk fo...

Candice E. Van Skike, Stacy A. Hussong, Stephen F. Hernandez, Andy Q. Banh, Nicholas DeRosa et al. (see pages [4305–4320][1]) Disruption of cerebral blood flow and its regulation by neural activity (neurovascular coupling) occur early in Alzheimer's disease (AD), often before other symptoms

Release of neuropeptides from dense core vesicles (DCVs) is essential for neuromodulation. Compared with the release of small neurotransmitters, much less is known about the mechanisms and proteins contributing to neuropeptide release. By optogenetics, behavioral analysis, electrophysiology, electron microscopy, and live imaging, we show that synapsin SNN-1 is required for cAMP-dependent neuropeptide release in Caenorhabditis elegans hermaphrodite cholinergic motor neurons. In synapsin mutants, behaviors induced by the photoactivated adenylyl cyclase bPAC, which we previously showed to depend on ACh and neuropeptides ([Steuer Costa et al., 2017][1]), are altered as in animals with reduced cAMP. Synapsin mutants have slight alterations in synaptic vesicle (SV) distribution; however, a defect in SV mobilization was apparent after channelrhodopsin-based photostimulation. DCVs were largely affected in snn-1 mutants: DCVs were ∼30% reduced in synaptic terminals, and their contents not released following bPAC st...

The brain functions through coordinated activity among distributed regions. Wide-field calcium imaging, combined with improved genetically encoded calcium indicators, allows sufficient signal-to-noise ratio and spatiotemporal resolution to afford a unique opportunity to capture cortex-wide dynamics on a moment-by-moment basis in behaving animals. Recent applications of this approach have been uncovering cortical dynamics at unprecedented scales during various cognitive processes, ranging from relatively simple sensorimotor integration to more complex decision-making tasks. In this review, we will highlight recent scientific advances enabled by wide-field calcium imaging in behaving mice. We then summarize several technical considerations and future opportunities for wide-field imaging to uncover large-scale circuit dynamics.