P2X7 is a subtype of ATP-gated channels that is highly expressed in astrocytes, microglia, and other immune cells. Activation of P2X7 purinoceptors by ATP or 3′- O -(4-benzoyl)-benzoyl ATP (BzATP) induces the formation of cytolytic pores and provokes release of interleukin-1β from immune cells. We investigated the actions of other endogenous nucleotides on recombinant and microglial P2X7 receptors using electrophysiology, fluorescence imaging, and interleukin-1β release measurement. We found that initial application of ADP or AMP to Xenopus oocytes expressing P2X7 receptors was ineffective. However, when ADP and AMP, but not UTP or adenosine, were applied after a brief exposure to ATP or BzATP, they activated P2X7 receptors in a dose-dependent manner. Moreover, responses to ADP and AMP were also elicited after exposure to low concentrations of ATP and were recorded several minutes after removal of ATP from the extracellular medium. Whole-cell recordings from mouse microglial cells showed that significant r...

Humans deftly parse statistics from sequences. Some theories posit that humans learn these statistics by forming cognitive maps, or underlying representations of the latent space which links items in the sequence. Here, an item in the sequence is a node, and the probability of transitioning between two items is an edge. Sequences can then be generated from walks through the latent space, with different spaces giving rise to different sequence statistics. Individual or group differences in sequence learning can be modeled by changing the time scale over which estimates of transition probabilities are built, or in other words, by changing the amount of temporal discounting. Latent space models with temporal discounting bear a resemblance to models of navigation through Euclidean spaces. However, few explicit links have been made between predictions from Euclidean spatial navigation and neural activity during human sequence learning. Here, we use a combination of behavioral modeling and intracranial encephalo...

Perception is facilitated by a hierarchy of expectations generated from context and prior knowledge. In auditory processing, violations of local (within-trial) expectations elicit a mismatch negativity (MMN), while violations of global (across-trial) expectations elicit a later positive component (P300). This result is taken as evidence of prediction errors ascending through the expectation hierarchy. However, in language comprehension, there is no evidence that violations of semantic expectations across local-global levels similarly elicit a sequence of hierarchical error signals, thus drawing into question the putative link between event-related potentials (ERPs) and prediction errors. We investigated the neural basis of such hierarchical expectations of semantics in a word-pair priming paradigm. By manipulating the overall proportion of related or unrelated word-pairs across the task, we created two global contexts that differentially encouraged strategic use of primes. Across two experiments, we replic...

Stressful life events are important contributors to relapse in recovering cocaine addicts, but the mechanisms by which they influence motivational systems are poorly understood. Studies suggest that stress may “set the stage” for relapse by increasing the sensitivity of brain reward circuits to drug-associated stimuli. We examined the effects of stress and corticosterone on behavioral and neurochemical responses of rats to a cocaine prime after cocaine self-administration and extinction. Exposure of rats to acute electric footshock stress did not by itself reinstate drug-seeking behavior but potentiated reinstatement in response to a subthreshold dose of cocaine. This effect of stress was not observed in adrenalectomized animals, and was reproduced in nonstressed animals by administration of corticosterone at a dose that reproduced stress-induced plasma levels. Pretreatment with the glucocorticoid receptor antagonist RU38486 did not block the corticosterone effect. Corticosterone potentiated cocaine-induce...

Processing of olfactory information is modulated by centrifugal projections from cortical areas, yet their behavioral relevance and underlying neural mechanisms remain unclear in most cases. The anterior olfactory nucleus (AON) is part of the olfactory cortex, and its extensive connections to multiple upstream and downstream brain centers place it in a prime position to modulate early sensory information in the olfactory system. Here, we show that optogenetic activation of AON neurons in awake male and female mice was not perceived as an odorant equivalent cue. However, AON activation during odorant presentation reliably suppressed behavioral odor responses. This AON-mediated effect was fast and constant across odors and concentrations. Likewise, activation of glutamatergic AON projections to the olfactory bulb (OB) transiently inhibited the excitability of mitral/tufted cells (MTCs) that relay olfactory input to the cortex. Single-unit MTC recordings revealed that optogenetic activation of glutamatergic A...

Transcranial random noise stimulation (tRNS) has been shown to significantly improve visual perception. Previous studies demonstrated that tRNS delivered over cortical areas acutely enhances visual contrast detection of weak stimuli. However, it is currently unknown whether tRNS-induced signal enhancement could be achieved within different neural substrates along the retino-cortical pathway. In 3 experimental sessions, we tested whether tRNS applied to the primary visual cortex(V1) and/or to the retina improves visual contrast detection. We first measured visual contrast detection threshold (VCT; N=24, 16females) during tRNS delivery separately over V1 and over the retina, determined the optimal tRNS intensities for each individual(ind-tRNS), and retested the effects of ind-tRNS within the sessions. We further investigated whether we could reproduce the ind-tRNS-induced modulation on a different session (N=19, 14females). Finally, we tested whether the simultaneous application of ind-tRNS to the retina an...

The ability to actively locate potential threats in our environment is highly adaptive. To investigate mediating neural mechanisms, we designed a visual search task in which central cues signaled future location and emotional expression (angry or neutral) of a target face. Cues predicting angry targets accelerated subsequent attention shifts, indicating that endogenous signals predicting threatening events can prime the spatial attention network. Functional imaging showed that spatially informative cues activated the fusiform gyrus (FG) as well as frontoparietal components of the spatial attention network, including intraparietal sulcus (IPS) and frontal eye field (FEF), whereas cues predicting angry faces also activated limbic areas, including the amygdala. Anatomically overlapping, additive effects of spatial and emotional cuing were identified in the IPS, FEFs, and FG, regions that also displayed augmented connectivity with the amygdala after cues predicting angry faces. These data highlight a key role ...

Spoken language comprehension in a second language (L2) depends on the ability to map an acoustic signal onto one of two co-existing acoustic-perceptual systems. This mapping process commonly occurs in noisy listening conditions. The neural systems that...

Homeostatic plasticity stabilizes firing rates of neurons, but the pressure to restore low activity rates can significantly alter synaptic and cellular properties. Most previous studies of homeostatic readjustment to complete activity silencing in rodent forebrain have examined changes after two days of deprivation, but it is known that longer periods of deprivation can produce adverse effects. To better understand the mechanisms underlying these effects and to address how presynaptic as well as postsynaptic compartments change during homeostatic plasticity, we subjected mouse cortical slice cultures to a more severe five-day deprivation paradigm. We developed and validated a computational framework to measure the number and morphology of presynaptic and postsynaptic compartments from super resolution light microscopy images of dense cortical tissue. Using these tools, combined with electrophysiological miniature excitatory postsynaptic current measurements, and synaptic imaging at the electron microscopy ...