Faculty Bibliography

Neurons in visual cortex vary in their orientation selectivity. We measured responses of V1 and V2 cells to orientation mixtures and fit them with a model whose stimulus selectivity arises from the combined effects of filtering, suppression, and response nonlinearity. The model explains the diversity of orientation selectivity with neuron-to-neuron variability in all three mechanisms, of which variability in the orientation bandwidth of linear filtering is the most important. The model also accounts for the cells' diversity of spatial frequency selectivity. Tuning diversity is matched to the needs of visual encoding. The orientation content found in natural scenes is diverse, and neurons with different selectivities are adapted to different stimulus configurations. Single orientations are better encoded by highly selective neurons, while orientation mixtures are better encoded by less selective neurons. A diverse population of neurons therefore provides better overall discrimination capabilities for natural images than any homogeneous population.

The Neurodata Without Borders (NWB) initiative promotes data standardization in neuroscience to increase research reproducibility and opportunities. In the first NWB pilot project, neurophysiologists and software developers produced a common data format for recordings and metadata of cellular electrophysiology and optical imaging experiments. The format specification, application programming interfaces, and sample datasets have been released.

The nucleus accumbens (NAc) is a key component of the brain reward system, and it is composed of core and shell subregions. Glutamate transmission through AMPA-type receptors in both core and shell of the NAc has been shown to regulate reward- and aversion-type behaviors. Previous studies have additionally demonstrated a role for AMPA receptor signaling in the NAc in chronic pain states. Here, we show that persistent neuropathic pain, modeled by spared nerve injury (SNI), selectively increases the numbers of GluA1 subunits of AMPA receptors at the synapse of both core and shell subregions. Such increases are not observed, however, for the GluA2 subunits. Furthermore, we find that phosphorylation at Ser845-GluA1 is increased by SNI at both core and shell subregions. These results demonstrate that persistent neuropathic pain increases AMPA receptor delivery to the synapse in both NAc core and shell, implying a role for AMPA receptor signaling in these regions in pain states.

Circuit hyperexcitability has been implicated in neuropathology of Fragile X syndrome, the most common inheritable cause of intellectual disability. Yet, how canonical unitary circuits are affected in this disorder remains poorly understood. Here, we examined this question in the context of the canonical feed-forward inhibitory circuit formed by the Temporoammonic (TA) branch of the perforant path, the major cortical input to the hippocampus. TA feed-forward circuits exhibited a marked increase in excitation/excitation ratio and major functional defects in spike modulation tasks in Fmr1 KO mice, a Fragile X mouse model. Changes in feed-forward circuits were caused specifically by inhibitory, but not excitatory, synapse defects. TA-associated inhibitory synapses exhibited increase in paired-pulse ratio and in the coefficient of variation of IPSPs, consistent with decreased GABA release probability. TA-associated inhibitory synaptic transmission in Fmr1 KO mice was also more sensitive to inhibition of GABAB receptors, suggesting an increase in presynaptic GABAB receptor (GABAB R) signaling. Indeed, the differences in inhibitory synaptic transmission between Fmr1 KO and WT mice were eliminated by a GABAB R antagonist. Inhibition of GABAB Rs or selective activation of presynaptic GABAB Rs also abolished the differences in the TA feed-forward circuit properties between Fmr1 KO and WT mice. These GABAB R-mediated defects were circuit-specific and were not observed in the Schaffer collateral pathway-associated inhibitory synapses. Our results suggest that the inhibitory synapse dysfunction in the cortical-hippocampal pathway of Fmr1 KO mice causes hyperexcitability and feed-forward circuit defects, which are mediated in part by a presynaptic GABAB R-dependent reduction in GABA release

The examination of functional connectivity in fMRI data collected during task-free "rest" has provided a powerful tool for studying functional brain organization. Limitations of this approach include susceptibility to head motion artifacts and participant drowsiness or sleep. These issues are especially relevant when studying young children or clinical populations. Here we introduce a movie paradigm, Inscapes, that features abstract shapes without a narrative or scene-cuts. The movie was designed to provide enough stimulation to improve compliance related to motion and wakefulness while minimizing cognitive load during the collection of functional imaging data. We compare Inscapes to eyes-open rest and to age-appropriate movie clips in healthy adults (Ocean's Eleven, n=22) and a pilot sample of typically developing children ages 3-7 (Fantasia, n=13). Head motion was significantly lower during both movies relative to rest for both groups. In adults, movies decreased the number of participants who self-reported sleep. Intersubject correlations, used to quantify synchronized, task-evoked activity across movie and rest conditions in adults, involved less cortex during Inscapes than Ocean's Eleven. To evaluate the effect of movie-watching on intrinsic functional connectivity networks, we examined mean functional connectivity using both whole-brain functional parcellation and network-based approaches. Both inter- and intra-network metrics were more similar between Inscapes and Rest than between Ocean's Eleven and Rest, particularly in comparisons involving the default network. When comparing movies to Rest, the mean functional connectivity of somatomotor, visual and ventral attention networks differed significantly across various analyses. We conclude that low-demand movies like Inscapes may represent a useful intermediate condition between task-free rest and typical narrative movies while still improving participant compliance. Inscapes is publicly available for download at headspacestudios.org/inscapes.

Enhancers, critical determinants of cellular identity, are commonly recognized by correlative chromatin marks and gain-of-function potential, although only loss-of-function studies can demonstrate their requirement in the native genomic context. Previously, we identified an erythroid enhancer of human BCL11A, subject to common genetic variation associated with the fetal haemoglobin level, the mouse orthologue of which is necessary for erythroid BCL11A expression. Here we develop pooled clustered regularly interspaced palindromic repeat (CRISPR)-Cas9 guide RNA libraries to perform in situ saturating mutagenesis of the human and mouse enhancers. This approach reveals critical minimal features and discrete vulnerabilities of these enhancers. Despite conserved function of the composite enhancers, their architecture diverges. The crucial human sequences appear to be primate-specific. Through editing of primary human progenitors and mouse transgenesis, we validate the BCL11A erythroid enhancer as a target for fetal haemoglobin reinduction. The detailed enhancer map will inform therapeutic genome editing, and the screening approach described here is generally applicable to functional interrogation of non-coding genomic elements.

Fate determination in the mammalian telencephalon, with its diversity of neuronal subtypes and relevance to neuropsychiatric disease, remains a critical area of study in neuroscience. Most studies investigating this topic focus on the diversity of neural progenitors within spatial and temporal domains along the lateral ventricles. Often overlooked is whether the location of neurogenesis within a fate-restricted domain is associated with, or instructive for, distinct neuronal fates. Here, we use in vivo fate mapping and the manipulation of neurogenic location to demonstrate that apical versus basal neurogenesis influences the fate determination of major subgroups of cortical interneurons derived from the subcortical telencephalon. Somatostatin-expressing interneurons arise mainly from apical divisions along the ventricular surface, whereas parvalbumin-expressing interneurons originate predominantly from basal divisions in the subventricular zone. As manipulations that shift neurogenic location alter interneuron subclass fate, these results add an additional dimension to the spatial-temporal determinants of neuronal fate determination.

An efficient total synthesis of the unusual polyketide portentol is reported. Three boron aldol reactions were used to assemble the linear carbon chain of the natural product, which contains two challenging anti-anti stereotriads. A biomimetic double cyclization cascade, triggered by an oxidation, then afforded portentol and its known dehydration product, anhydroportentol. The biosynthesis of portentol and the biosynthetic relevance of our key step are discussed.

The response properties of neurons in the early stages of the visual system can be described using the rectified responses of a set of self-similar, spatially shifted linear filters. In macaque primary visual cortex (V1), simple cell responses can be captured with a single filter, whereas complex cells combine a set of filters, creating position invariance. These filters cannot be estimated using standard methods, such as spike-triggered averaging. Subspace methods like spike-triggered covariance can recover multiple filters but require substantial amounts of data, and recover an orthogonal basis for the subspace in which the filters reside, rather than the filters themselves. Here, we assume a linear-nonlinear-linear-nonlinear (LN-LN) cascade model in which the first LN stage consists of shifted ("convolutional") copies of a single filter, followed by a common instantaneous nonlinearity. We refer to these initial LN elements as the "subunits" of the receptive field, and we allow two independent sets of subunits, each with its own filter and nonlinearity. The second linear stage computes a weighted sum of the subunit responses and passes the result through a final instantaneous nonlinearity. We develop a procedure to directly fit this model to electrophysiological data. When fit to data from macaque V1, the subunit model significantly outperforms three alternatives in terms of cross-validated accuracy and efficiency, and provides a robust, biologically plausible account of receptive field structure for all cell types encountered in V1. SIGNIFICANCE STATEMENT: We present a new subunit model for neurons in primary visual cortex that significantly outperforms three alternative models in terms of cross-validated accuracy and efficiency, and provides a robust and biologically plausible account of the receptive field structure in these neurons across the full spectrum of response properties.