The ability to separate background noise from relevant acoustic signals is essential for appropriate sound-driven behavior in natural environments. Examples of this separation are apparent in the auditory system, where neural responses to behaviorally relevant stimuli become increasingly noise invariant along the ascending auditory pathway. However, the mechanisms that underlie this reduction in responses to background noise are not well understood. To address this gap in knowledge, we first evaluated the effects of auditory cortical inactivation on mice of both sexes trained to perform a simple auditory signal-in-noise detection task and found that outputs from the auditory cortex are important for the detection of auditory stimuli in noisy environments. Next, we evaluated the contributions of the two most common cortical inhibitory cell types, parvalbumin-expressing (PV+) and somatostatin-expressing (SOM+) interneurons, to the perception of masked auditory stimuli. We found that inactivation of either PV...

Disorders of the medial temporal lobe (MTL) adversely affect visual working memory (vWM) performance, including feature binding. It is unclear whether these impairments generalize across visual dimensions or are specifically spatial. To address this issue, we compared performance in two tasks of 13 epilepsy patients, who had undergone a temporal lobectomy, and 15 healthy controls. In the vWM task, participants recalled the color of one of two polygons, previously displayed side by side. At recall, a location or shape probe identified the target. In the perceptual task, participants estimated the centroid of three visible disks. Patients recalled the target color less accurately than healthy controls because they frequently swapped the nontarget with the target color. Moreover, healthy controls and right temporal lobectomy patients made more swap errors following shape than space probes. Left temporal lobectomy patients, showed the opposite pattern of errors instead. Patients and controls performed similarl...

Cisplatin-induced ototoxicity can be partially attributed to excessive reactive oxygen species (ROS) production, and agmatine is well-known for the activation of the phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT) pathway to inhibit ROS production. Whether agmatine could be used to alleviate cisplatin-induced ototoxicity is investigated. Cisplatin-exposed House Ear Institute-Organ of Corti 1 (HEI-OC1) cells and cochlear explants showed increased ROS production detected by 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) staining and decreased cell viability detected by Cell Counting Kit-8 (CCK-8) or Myosin 7a staining, which could be reversed by the agmatine pretreatment. Cisplatin intraperitoneally injected C57BL/6 mice demonstrated damaged auditory function as indicated by distortion products otoacoustic emissions (DPOAEs) and auditory brainstem response (ABR) assays, and trans-tympanically administrated agmatine in the left ears could partly prevent the auditory function loss. Mechanisticall...

The human sensorimotor system is sensitive to both limb-related prediction errors and task-related performance errors. Prediction error signals are believed to drive implicit refinements to motor plans. However, an understanding of the mechanisms that performance errors stimulate has remained unclear largely because their effects have not been probed in isolation from prediction errors. Diverging from past work, we induced performance errors independent of prediction errors by shifting the location of a reach target but keeping the intended and actual kinematic consequences of the motion matched. Our first two experiments revealed that rather than implicit learning, motor adjustments in response to performance errors reflect the use of deliberative, volitional strategies. Our third experiment revealed a potential dissociation of performance-error-driven strategies based on error size. Specifically, behavioral changes following large errors were consistent with goal-directed or model-based control, known to...

Overlap between events can lead to interference because of a trade-off between encoding the present event and retrieving the past event. Temporal context information, “when” something occurred, a defining feature of episodic memory, can cue retrieval of a past event. However, the influence of temporal overlap, or proximity in time, on the mechanisms of interference is unclear. Here, by identifying brain states using scalp eEEG from male and female human subjects, we show the extent to which temporal overlap promotes interference and induces retrieval. In this experiment, subjects were explicitly directed to either encode the present event or retrieve a past, overlapping event while perceptual input was held constant. We find that the degree of temporal overlap between events leads to selective interference. Specifically, greater temporal overlap between two events leads to impaired memory for the past event selectively when the top-down goal is to encode the present event. Using pattern classification anal...

To explore whether the thalamus participates in lexical status (word vs. nonword) processing during spoken word production, we recorded local field potentials from the ventral lateral thalamus in 11 essential tremor patients (three females) undergoing thalamic deep brain stimulation lead implantation during a visually cued word- and nonword-reading aloud task. We observed task-related beta (12-30 Hz) activity decreases that were preferentially time-locked to stimulus presentation, and broadband gamma (70-150 Hz) activity increases, which are thought to index increased multi-unit spiking activity, occurring shortly before and predominantly time-locked to speech onset. We further found that thalamic beta activity decreases bilaterally were greater when nonwords were read, demonstrating bilateral sensitivity to lexical status that likely reflects the tracking of task effort; in contrast, greater nonword-related increases in broadband gamma activity were observed only on the left, demonstrating lateralization ...

During visually guided behaviors, mere hundreds of milliseconds can elapse between a sensory input and its associated behavioral response. How spikes occurring at different times are integrated to drive perception and action remains poorly understood. We delivered random trains of optogenetic stimulation (white noise) to excite inhibitory interneurons in V1 of mice of both sexes while they performed a visual detection task. We then performed a reverse correlation analysis on the optogenetic stimuli to generate a neuronal-behavioral kernel: an unbiased, temporally-precise estimate of how suppression of V1 spiking at different moments around the onset of a visual stimulus affects detection of that stimulus. Electrophysiological recordings enabled us to capture the effects of optogenetic stimuli on V1 responsivity and revealed that the earliest stimulus-evoked spikes are preferentially weighted for guiding behavior. These data demonstrate that white noise optogenetic stimulation is a powerful tool for underst...

Habituated animals retain a latent capacity for robust engagement with familiar stimuli. In most instances, the ability to override habituation is best explained by postulating that habituation arises from the potentiation of inhibitory inputs onto stimulus-encoding assemblies and that habituation override occurs through disinhibition. Previous work has shown that inhibitory plasticity contributes to specific forms of olfactory and gustatory habituation in Drosophila . Here we analyze how exposure to a novel stimulus causes override of gustatory (proboscis-extension reflex or “PER”) habituation. While brief sucrose contact with tarsal hairs causes naïve Drosophila to extend their proboscis, persistent exposure reduces PER to subsequent sucrose stimuli. We show that in so habituated animals, either brief exposure of the proboscis to yeast or direct thermogenetic activation of sensory neurons restores PER response to tarsal sucrose stimulation. Similar override of PER habituation can also be induced by brief...

Hypothalamic melanin-concentrating hormone (MCH) neurons are important regulators of multiple physiological processes, such as sleep, feeding, and memory. Despite the increasing interest in their neuronal functions, the molecular mechanism underlying MCH neuron development remains poorly understood. We report that a three-dimensional culture of mouse embryonic stem cells (mESCs) can generate hypothalamic-like tissues containing MCH-positive neurons, which reproduce morphologic maturation, neuronal connectivity, and neuropeptide/neurotransmitter phenotype of native MCH neurons. Using this in vitro system, we demonstrate that Hedgehog (Hh) signaling serves to produce major neurochemical subtypes of MCH neurons characterized by the presence or absence of cocaine- and amphetamine-regulated transcript (CART). Without exogenous Hh signals, mESCs initially differentiated into dorsal hypothalamic/prethalamic progenitors and finally into MCH+CART+ neurons through a specific intermediate progenitor state. Conversely...

Cortical GABAergic interneurons have been shown to fulfil important roles by inhibiting excitatory principal neurons. Recent transcriptomic studies have confirmed seminal discoveries that used anatomic and electrophysiological methods highlighting the existence of multiple different classes of GABAergic interneurons. Although some of these studies have emphasized that inter-regional differences may exist for a given class, the extent of such differences remains unknown. To address this problem, we used single-cell Patch-RNAseq to characterize neuropeptide Y (NPY)-positive GABAergic interneurons in superficial layers of the primary auditory cortex (AC) and in distal layers of area CA3 in mice. We found that more than 300 genes are differentially expressed in NPY-positive neurons between these two brain regions. For example, the AMPA receptor (AMPAR) auxiliary subunit Shisa9/CKAMP44 and the 5HT2a receptor (5HT2aR) are significantly higher expressed in auditory NPY-positive neurons. These findings guided us t...