Limb apraxia (LA) refers to a high-order motor disorder characterized by the inability to reproduce transitive actions on commands or after observation. Studies demonstrate that action observation and action execution activate the same networks in the human brain, and provides an onlooker’s motor system with appropriate cognitive, motor and sensory-motor cues to flexibly implementing action-sequences and gestures. Tellingly, the temporal dynamics of action monitoring has never been explored in people suffering from LA. To fill this gap, we studied the electro-cortical signatures of error observation in human participants suffering from acquired left-brain lesions with (LA+) and without (LA–) LA, and in a group of healthy controls (H). EEG was acquired while participants observed from a first-person perspective (1PP) an avatar performing correct or incorrect reach-to-grasp a glass action in an immersive-virtual environment. Alterations of typical EEG signatures of error observation in time (early error posi...

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...

Neurons in the dorsolateral prefrontal cortex (dlPFC) and posterior parietal cortex (PPC) are activated by different cognitive tasks and respond differently to the same stimuli depending on task. The conjunctive representations of multiple tasks in nonlinear fashion in single neuron activity, is known as nonlinear mixed selectivity (NMS). Here, we compared NMS in a working memory task in areas 8a and 46 of the dlPFC and 7a and lateral intraparietal cortex (LIP) of the PPC in macaque monkeys. NMS neurons were more frequent in dlPFC than in PPC and this was attributed to more cells gaining selectivity in the course of a trial. Additionally, in our task, the subjects’ behavioral performance improved within a behavioral session as they learned the session-specific statistics of the task. The magnitude of NMS in the dlPFC also increased as a function of time within a single session. On the other hand, we observed minimal rotation of population responses and no appreciable differences in NMS between correct and ...

Temporal processing of complex sounds is a fundamental and complex task in hearing and a prerequisite for processing and understanding vocalization, speech, and prosody. Here, we studied response properties of neurons in the inferior colliculus (IC) in mice lacking Cacna2d3 , a risk gene for autism spectrum disorders (ASDs). The α2δ3 auxiliary Ca2+ channel subunit encoded by Cacna2d3 is essential for proper function of glutamatergic synapses in the auditory brainstem. Recent evidence has shown that much of auditory feature extraction is performed in the auditory brainstem and IC, including processing of amplitude modulation (AM). We determined both spectral and temporal properties of single- and multi-unit responses in the IC of anesthetized mice. IC units of α2δ3−/− mice showed normal tuning properties yet increased spontaneous rates compared with α2δ3+/+. When stimulated with AM tones, α2δ3−/− units exhibited less precise temporal coding and reduced evoked rates to higher modulation frequencies (fm). Whe...

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...

In the article, “Automated Detection and Localization of Synaptic Vesicles in Electron Microscopy Images,” by Barbara Imbrosci, Dietmar …

We assessed similarities and differences in the electrographic signatures of local field potentials evoked by different pharmacological agents in zebrafish larvae. We then compared and contrasted these characteristics with what is known from electrophysiological studies of seizures and epilepsy in mammals, including humans. Ultimately, our aim was to phenotype neurophysiological features of drug-induced seizures in larval zebrafish for expanding knowledge on the translational potential of this valuable alternative to mammalian models. Local field potentials were recorded from the midbrain of 4-day old zebrafish larvae exposed to a pharmacologically diverse panel of seizurogenic compounds, and the outputs of these recordings were assessed using frequency domain analysis. This included analysis of changes occurring within various spectral frequency bands of relevance to mammalian CNS circuit pathophysiology. From these analyses, there were clear differences in the frequency spectra of drug-exposed local fiel...

The neural basis of attention is thought to involve the allocation of limited neural resources. However, the quantitative validation of this hypothesis remains challenging. Here, we provide quantitative evidence that the nonuniform allocation of neural resources across the whole cerebral gray matter reflects the broad-task process of sustained attention. We propose a neural measure for the nonuniformity of whole-cerebral allocation using functional magnetic resonance imaging. We found that this measure was significantly correlated with conventional indicators of attention level, such as task difficulty and pupil dilation. We further found that the broad-task neural correlates of the measure belong to fronto-parietal and dorsal attention networks. Finally, we found that patients with attention-deficit/hyperactivity disorder showed abnormal decreases in the level of the proposed measure reflecting the executive dysfunction. This study proposes a neuromarker suggesting that the nonuniform allocation of neural...

To better understand complex systems, such as the brain, studying the interactions between multiple brain regions is imperative. Such experiments often require delineation of multiple brain regions on microscopic images based on pre-existing brain atlases. Experiments examining the relationships of multiple regions across the brain have traditionally relied on manual plotting of regions. This process is very intensive and becomes untenable with a large number of regions of interest. To reduce the amount of time required to process multi-region datasets, several tools for atlas registration have been developed; however, these tools are often inflexible to tissue type, only supportive of a limited number of atlases and orientation, require considerable computational expertise, or are only compatible with certain types of microscopy. To address the need for a simple yet extensible atlas registration tool we have developed FASTMAP, a flexible atlas segmentation tool for multi-area processing. We demonstrate it...

Here we investigate stimulus generalization in a cerebellar learning paradigm, called eyeblink conditioning. Mice were conditioned to close their eyes in response to a 10 kHz tone by repeatedly pairing this tone with an air puff to the eye 250 ms after tone onset. After ten consecutive days of training, when mice showed reliable conditioned eyelid responses to the 10 kHz tone, we started to expose them to tones with other frequencies, ranging from 2 to 20 kHz. We found that mice had a strong generalization gradient, whereby the probability and amplitude of conditioned eyelid responses gradually decreases depending on the dissimilarity with the 10 kHz tone. Tones with frequencies closest to 10kHz evoked the most and largest conditioned eyelid responses and each step away from the 10 kHz tone resulted in fewer and smaller conditioned responses. In addition, we found that tones with lower frequencies resulted in conditioned responses that peaked earlier after tone onset compared to those to tones with higher ...