When animals repeatedly receive a combination of neutral conditional stimulus (CS) and aversive unconditional stimulus (US), they learn the relationship between CS and US, and show conditioned fear responses after CS. They show passive responses such as freezing or panic movements (classical or Pavlovian fear conditioning), or active behavioral responses to avoid aversive stimuli (active avoidance). Previous studies suggested the roles of the cerebellum in classical fear conditioning but it remains elusive whether the cerebellum is involved in active avoidance conditioning. In this study, we analyzed the roles of cerebellar neural circuits during active avoidance in adult zebrafish. When pairs of CS (light) and US (electric shock) were administered to wild-type zebrafish, about half of them displayed active avoidance. The expression of botulinum toxin, which inhibits the release of neurotransmitters, in cerebellar granule cells (GCs) or Purkinje cells (PCs) did not affect conditioning-independent swimming ...

Numerous theories propose a key role for brain oscillations in visual perception. Most of these theories postulate that sensory information is encoded in specific oscillatory components (e.g., power or phase) of specific frequency bands. These theories are often tested with whole-brain recording methods of low spatial resolution (EEG or MEG), or depth recordings that provide a local, incomplete view of the brain. Opportunities to bridge the gap between local neural populations and whole-brain signals are rare. Here, using representational similarity analysis (RSA) in human participants we explore which MEG oscillatory components (power and phase, across various frequency bands) correspond to low or high-level visual object representations, using brain representations from fMRI, or layer-wise representations in seven recent deep neural networks (DNNs), as a template for low/high-level object representations. The results showed that around stimulus onset and offset, most transient oscillatory signals correla...

Alzheimer’s disease (AD) is an incurable neurodegenerative disorder and a major cause of dementia. Some of the hallmarks of AD include presence of amyloid plaques in brain parenchyma, calcium dysregulation within individual neurons, and neuroinflammation. A promising therapeutic would reverse or stymie these pathophysiologies in an animal model of AD. We tested the effect of NB-02, previously known as DA-9803, a novel multimodal therapeutic, on amyloid deposition, neuronal calcium regulation and neuroinflammation in 8- to 10-month-old APP/PS1 mice, an animal model of AD. In vivo multiphoton microscopy revealed that two-month-long administration of NB-02 halted amyloid plaque deposition and cleared amyloid in the cortex. Postmortem analysis verified NB-02-dependent decrease in plaque deposition in the cortex as well as hippocampus. Furthermore, drug treatment reversed neuronal calcium elevations, thus restoring neuronal function. Finally, NB-02 restored spine density and transformed the morphology of astroc...

AMPA receptor (AMPAR) mobility within synapses has been extensively studied in vitro . However, whether similar mobility properties apply to AMPARs in vivo has yet to be determined. Here, we use two-photon fluorescence recovery after photobleaching (FRAP) to study AMPAR mobility within individual dendritic spines in live animals using an overexpression vector. We demonstrate the existence of mobile and immobile fractions of AMPARs across multiple cortical regions and layers. Additionally, we find that AMPAR mobility can be altered in vivo in response to administration of corticosterone, a condition that mimics exposure to stress.

The isocortex of all mammals studied to date shows a progressive increase in the amount and continuity of background activity during early development. In humans the transition from a discontinuous (mostly silent, intermittently bursting) cortex to one that is continuously active is complete soon after birth and is a critical prognostic indicator. In the visual cortex of rodents this switch from discontinuous to continuous background activity occurs during the 2 d before eye-opening, driven by activity changes in relay thalamus. The factors that regulate the timing of continuity development, which enables mature visual processing, are unknown. Here, we test the role of the retina, the primary input, in the development of continuous spontaneous activity in the visual cortex of mice using depth electrode recordings from enucleated mice in vivo . Bilateral enucleation at postnatal day (P)6, one week before the onset of continuous activity, acutely silences cortex, yet firing rates and early oscillations retur...

Traumatic brain injury (TBI) causes cellular and molecular alterations that contribute to neuropsychiatric disease and epilepsy. GABAergic dysfunction figures prominently in the pathophysiology of TBI, yet the effects of TBI on tonic inhibition in hippocampus remain uncertain. We used a mouse model of severe TBI [controlled cortical impact (CCI)] to investigate GABAergic signaling in dentate gyrus granule cells (DGGCs). Basal tonic GABA currents were not affected by CCI. However, tonic currents induced by the δ subunit-selective GABAA receptor agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP; 10 μm) were reduced by 44% in DGGCs ipsilateral to CCI (CCI-ipsi), but not in contralateral DGGCs. Reduced THIP currents were apparent one week after injury and persisted up to 15 weeks. The frequency of spontaneous IPSCs (sIPSCs) was reduced in CCI-ipsi cells, but the amplitude and kinetics of sIPSCs were unaffected. Immunohistochemical analysis showed reduced expression of GABAA receptor δ subunits and G...

Nociceptive stimuli disrupt sleep, but may, or may not, entail an arousal. While arousal reactions go along with the activation of a widespread cortical network, the factors enabling such activation remain unknown. Here we used intracranial EEG (iEEG) in humans to test the relation between the cortical activity immediately preceding a noxious stimulus and the capacity of such a stimulus to trigger arousal. iEEG signals were analyzed during all-night sleep in 14 epileptic patients (4 women), who received laser stimuli slightly above their individual pain threshold. During 5-seconds preceding each stimulus, the functional correlation (spectral phase-coherence) between the main spinothalamic sensory area (posterior insula) and 12 other brain regions, grouped in 4 networks, as well as their spectral contents, were contrasted according to the presence of a stimulus-induced arousal, and then fed into a logistic regression model to assess their predictive value. Enhanced pre-stimulus phase-coherence between the s...

We developed a method for single-cell resolution longitudinal bioluminescence imaging of PERIOD (PER) protein and TIMELESS (TIM) oscillations in cultured male adult Drosophila brains that captures circadian circuit-wide cycling under simulated day/night cycles. Light input analysis confirms that CRYPTOCHROME (CRY) is the primary circadian photoreceptor and mediates clock disruption by constant light, and that eye light input is redundant to CRY. 3hr light phase delays (Friday) followed by 3hr light phase advances (Monday morning) simulate the common practice of staying up later at night on weekends, sleeping in later on weekend days then returning to standard schedule Monday morning (weekend light shift, WLS). PER and TIM oscillations are highly synchronous across all major circadian neuronal subgroups in unshifted light schedules for 11 days. In contrast, WLS significantly dampens PER oscillator synchrony and rhythmicity in most circadian neurons during and after exposure. Lateral ventral neuron (LNv) osc...

Cholinergic regulation of hippocampal circuit activity has been an active area of neurophysiological research for decades. The prominent cholinergic innervation of intrinsic hippocampal circuitry, potent effects of cholinomimetic drugs, and behavioral responses to cholinergic modulation of hippocampal circuitry have driven investigators to discover diverse cellular actions of acetylcholine in distinct sites within hippocampal circuitry. Further research has illuminated how these actions organize circuit activity to optimize encoding of new information, promote consolidation and coordinate this with recall of prior memories. The development of the hippocampal slice preparation was a major advance that accelerated knowledge of how hippocampal circuits functioned and how acetylcholine modulated these circuits. Using this preparation in the early 1980’s we made a serendipitous finding of a novel presynaptic inhibitory effect of acetylcholine on Schaffer collaterals, the projections from CA3 pyramidal neurons t...

The physiological role of the amyloid-precursor protein (APP) is insufficiently understood. Recent work has implicated APP in the regulation of synaptic plasticity. Substantial evidence exists for a role of APP and its secreted ectodomain APPsα in Hebbian plasticity. Here, we addressed the relevance of APP in homeostatic synaptic plasticity using organotypic tissue cultures prepared from APP-/- mice of both sexes. In the absence of APP, dentate granule cells failed to strengthen their excitatory synapses homeostatically. Homeostatic plasticity is rescued by amyloid-β (Aβ) and not by APPsα, and it is neither observed in APP+/+ tissue treated with β- or γ-secretase inhibitors nor in synaptopodin-deficient cultures lacking the Ca2+-dependent molecular machinery of the spine apparatus. Together, these results suggest a role of APP processing via the amyloidogenic pathway in homeostatic synaptic plasticity, representing a function of relevance for brain physiology as well as for brain states associated with inc...