Atoh1 drives the heterogeneity of the pontine nuclei neurons and promotes their differentiation.

Pontine nuclei (PN) neurons mediate the communication between the cerebral cortex andthe cerebellum to refine skilled motor functions. Prior studies showed that PN neurons fall into two subtypes based on their anatomic location and region-specific connectivity, but the extent of their heterogeneity and its molecular drivers remain unknown. Atoh1 encodes a transcription factor that is expressed in the PN precursors. We previously showed that partial loss of Atoh1 function in mice results in delayed PN development and impaired motor learning. In this study, we performed single-cell RNA sequencing to elucidate the cell state-specific functions of Atoh1 during PN development and found that Atoh1 regulates cell cycle exit, differentiation, migration, and survival of PN neurons. Our data revealed six previously not known PN subtypes that are molecularly and spatially distinct. We found that the PN subtypes exhibit differential vulnerability to partial loss of Atoh1 function, providing insights into the prominence of PN phenotypes in patients with ATOH1 missense mutations.

Antisense oligonucleotide therapy rescues disturbed brain rhythms and sleep in juvenile and adult mouse models of Angelman syndrome.

UBE3A encodes ubiquitin protein ligase E3A, and in neurons its expression from the paternal allele is repressed by the UBE3A antisense transcript (UBE3A-ATS). This leaves neurons susceptible to loss-of-function of maternal UBE3A. Indeed, Angelman syndrome, a severe neurodevelopmental disorder, is caused by maternal UBE3A deficiency. A promising therapeutic approach to treating Angelman syndrome is to reactivate the intact paternal UBE3A by suppressing UBE3A-ATS. Prior studies show that many neurological phenotypes of maternal Ube3a knockout mice can only be rescued by reinstating Ube3a expression in early development, indicating a restricted therapeutic window for Angelman syndrome. Here, we report that reducing Ube3a-ATS by antisense oligonucleotides in juvenile or adult maternal Ube3a knockout mice rescues the abnormal electroencephalogram (EEG) rhythms and sleep disturbance, two prominent clinical features of Angelman syndrome. Importantly, the degree of phenotypic improvement correlates with the increase of Ube3a protein levels. These results indicate that the therapeutic window of genetic therapies for Angelman syndrome is broader than previously thought, and EEG power spectrum and sleep architecture should be used to evaluate the clinical efficacy of therapies.

A weakened recurrent circuit in the hippocampus of Rett syndrome mice disrupts long-term memory representations.

Successful recall of a contextual memory requires reactivating ensembles of hippocampal cells that were allocated during memory formation. Altering the ratio of excitation-to-inhibition (E/I) during memory retrieval can bias cell participation in an ensemble and hinder memory recall. In the case of Rett syndrome (RTT), a neurological disorder with severe learning and memory deficits, the E/I balance is altered, but the source of this imbalance is unknown. Using in vivo imaging during an associative memory task, we show that during long-term memory retrieval, RTT CA1 cells poorly distinguish mnemonic context and form larger ensembles than wild-type mouse cells. Simultaneous multiple whole-cell recordings revealed that mutant somatostatin expressing interneurons (SOM) are poorly recruited by CA1 pyramidal cells and are less active during long-term memory retrieval in vivo. Chemogenetic manipulation revealed that reduced SOM activity underlies poor long-term memory recall. Our findings reveal a disrupted recurrent CA1 circuit contributing to RTT memory impairment.

A Disinhibitory Circuit for Contextual Modulation in Primary Visual Cortex.

Context guides perception by influencing stimulus saliency. Accordingly, in visual cortex, responses to a stimulus are modulated by context, the visual scene surrounding the stimulus. Responses are suppressed when stimulus and surround are similar but not when they differ. The underlying mechanisms remain unclear. Here, we use optical recordings, manipulations, and computational modeling to show that disinhibitory circuits consisting of vasoactive intestinal peptide (VIP)-expressing and somatostatin (SOM)-expressing inhibitory neurons modulate responses in mouse visual cortex depending on similarity between stimulus and surround, primarily by modulating recurrent excitation. When stimulus and surround are similar, VIP neurons are inactive, and activity of SOM neurons leads to suppression of excitatory neurons. However, when stimulus and surround differ, VIP neurons are active, inhibiting SOM neurons, which leads to relief of excitatory neurons from suppression. We have identified a canonical cortical disinhibitory circuit that contributes to contextual modulation and may regulate perceptual saliency.

Electrophysiological properties of isthmic neurons in frogs revealed by in vitro and in vivo studies.

The frog nucleus isthmi (parabigeminal nucleus in mammals) is a visually responsive, cholinergic and anatomically well-defined group of neurons in the midbrain. It shares reciprocal topographic projections with the ipsilateral optic tectum (superior colliculus in mammals) and strongly influences visual processing. Anatomical and biochemical information indicates the existence of distinct neural populations within the frog nucleus isthmi, which raises the question: are there electrophysiological distinctions between neurons that are putatively classified by their anatomical and biochemical properties? To address this question, we measured frog nucleus isthmi neuron cellular properties in vitro and visual response properties in vivo. No evidence for distinct electrophysiological classes of neurons was found. We thus conclude that, despite the anatomical and biochemical differences, the cells of the frog nucleus isthmi respond homogeneously to both current injections and simple visual stimuli.

Intricate phase diagram of a prevalent visual circuit reveals universal dynamics, phase transitions, and resonances.

Neural feedback-triads consisting of two feedback loops with a nonreciprocal lateral connection from one loop to the other are ubiquitous in the brain. We show analytically that the dynamics of this network topology are determined by algebraic combinations of its five synaptic weights. Exploration of network activity over the parameter space demonstrates the importance of the nonreciprocal lateral connection and reveals intricate behavior involving continuous transitions between qualitatively different activity states. In addition, we show that the response to periodic inputs is narrowly tuned around a center frequency determined by the effective synaptic parameters.