Faculty Bibliography

In this pilot study, we examined training effects of a computerized working memory program on resting state functional magnetic resonance imaging (fMRI) measures in children with neurofibromatosis type 1 (NF1). We contrasted pre- with post-training resting state fMRI and cognitive measures from 16 participants (nine males; 11.1 +/- 2.3 years) with NF1 and documented working memory difficulties. Using non-parametric permutation test inference, we found significant regionally specific differences (family-wise error corrected) in two of four voxel-wise resting state measures: fractional amplitude of low frequency fluctuations (indexing peak-to-trough intensity of spontaneous oscillations) and regional homogeneity (indexing local intrinsic synchrony). Some cognitive task improvement was observed as well. These preliminary findings suggest that regionally specific changes in resting state fMRI indices may be associated with treatment-related cognitive amelioration in NF1. Nevertheless, current results must be interpreted with caution pending independent controlled replication.

Neocortical inhibitory neurons exhibit remarkably diverse morphology, physiological properties and connectivity. Genetic access to molecularly defined subtypes of inhibitory neurons has aided their functional characterization in recent years. These studies have established that, instead of simply balancing excitatory neuron activity, inhibitory neurons actively shape excitatory circuits in a subtype-specific manner. We review the emerging view that inhibitory neuron subtypes perform context-dependent modulation of excitatory activity, as well as regulate experience-dependent plasticity of excitatory circuits. We then review the roles of neuromodulators in regulating the subtype-specific functions of inhibitory neurons. Finally, we discuss the idea that dysfunctions of inhibitory neuron subtypes may be responsible for various aspects of neurological disorders.

A dysfunctional endosomal pathway and abnormally enlarged early endosomes in neurons are an early characteristic of Down syndrome (DS) and Alzheimer's disease (AD). We have hypothesized that endosomal material can be released by endosomal multivesicular bodies (MVBs) into the extracellular space via exosomes to relieve neurons of accumulated endosomal contents when endosomal pathway function is compromised. Supporting this, we found that exosome secretion is enhanced in the brains of DS patients and a mouse model of the disease, and by DS fibroblasts. Furthermore, increased levels of the tetraspanin CD63, a regulator of exosome biogenesis, were observed in DS brains. Importantly, CD63 knockdown diminished exosome release and worsened endosomal pathology in DS fibroblasts. Taken together, these data suggest that increased CD63 expression enhances exosome release as an endogenous mechanism mitigating endosomal abnormalities in DS. Thus, the upregulation of exosome release represents a potential therapeutic goal for neurodegenerative disorders with endosomal pathology.

In amblyopia, a visual disorder caused by abnormal visual experience during development, the amblyopic eye (AE) loses visual sensitivity whereas the fellow eye (FE) is largely unaffected. Binocular vision in amblyopes is often disrupted by interocular suppression. We used 96-electrode arrays to record neurons and neuronal groups in areas V1 and V2 of six female macaque monkeys (Macaca nemestrina) made amblyopic by artificial strabismus or anisometropia in early life, as well as two visually normal female controls. To measure suppressive binocular interactions directly, we recorded neuronal responses to dichoptic stimulation. We stimulated both eyes simultaneously with large sinusoidal gratings, controlling their contrast independently with raised-cosine modulators of different orientations and spatial frequencies. We modeled each eye's receptive field at each cortical site using a difference of Gaussian envelopes and derived estimates of the strength of central excitation and surround suppression. We used these estimates to calculate ocular dominance separately for excitation and suppression. Excitatory drive from the FE dominated amblyopic visual cortex, especially in more severe amblyopes, but suppression from both the FE and AEs was prevalent in all animals. This imbalance created strong interocular suppression in deep amblyopes: increasing contrast in the AE decreased responses at binocular cortical sites. These response patterns reveal mechanisms that likely contribute to the interocular suppression that disrupts vision in amblyopes.SIGNIFICANCE STATEMENT Amblyopia is a developmental visual disorder that alters both monocular vision and binocular interaction. Using microelectrode arrays, we examined binocular interaction in primary visual cortex and V2 of six amblyopic macaque monkeys (Macaca nemestrina) and two visually normal controls. By stimulating the eyes dichoptically, we showed that, in amblyopic cortex, the binocular combination of signals is altered. The excitatory influence of the two eyes is imbalanced to a degree that can be predicted from the severity of amblyopia, whereas suppression from both eyes is prevalent in all animals. This altered balance of excitation and suppression reflects mechanisms that may contribute to the interocular perceptual suppression that disrupts vision in amblyopes.

We propose a new mechanism of sensory modulation through cutaneous dopaminergic signalling. We hypothesize that dopaminergic signalling contributes to differential cutaneous sensitivity in darker versus lighter pigmented humans and mouse strains. We show that thermal and mechanical cutaneous sensitivity is pigmentation dependent. Meta-analyses in humans and mice, along with our own mouse behavioural studies, reveal higher thermal sensitivity in pigmented skin relative to less-pigmented or albino skin. We show that dopamine from melanocytes activates the D1-like dopamine receptor on primary sensory neurons. Dopaminergic activation increases expression of the heat-sensitive TRPV1 ion channel and reduces expression of the mechanically-sensitive Piezo2 channel; thermal threshold is lower and mechanical threshold is higher in pigmented skin.

Eusocial insects use cuticular hydrocarbons as components of pheromones that mediate social behaviours, such as caste and nestmate recognition, and regulation of reproduction. In ants such as Harpegnathos saltator, the queen produces a pheromone which suppresses the development of workers' ovaries and if she is removed, workers can transition to a reproductive state known as gamergate. Here we functionally characterize a subfamily of odorant receptors (Ors) with a nine-exon gene structure that have undergone a massive expansion in ants and other eusocial insects. We deorphanize 22 representative members and find they can detect cuticular hydrocarbons from different ant castes, with one (HsOr263) that responds strongly to gamergate extract and a candidate queen pheromone component. After systematic testing with a diverse panel of hydrocarbons, we find that most Harpegnathos saltator Ors are narrowly tuned, suggesting that several receptors must contribute to detection and discrimination of different cuticular hydrocarbons important in mediating eusocial behaviour.Cuticular hydrocarbons (CHC) mediate the interactions between individuals in eusocial insects, but the sensory receptors for CHCs are unclear. Here the authors show that in ants such as H. saltator, the 9-exon subfamily of odorant receptors (HsOrs) responds to CHCs, and ectopic expression of HsOrs in Drosophila neurons imparts responsiveness to CHCs.

Excitatory amino acid transporters clear glutamate from the synaptic cleft and play a critical role in glutamatergic neurotransmission. Their differential roles in astrocytes, microglia, and neurons are poorly understood due in part to a lack of pharmacological tools that can be targeted to specific cells and tissues. We now describe a photoswitchable inhibitor, termed ATT, that interacts with the major mammalian forebrain transporters EAAT1-3 in a manner that can be reversibly switched between trans (high-affinity) and cis (low-affinity) configurations using light of different colors. In the dark, ATT competitively inhibited the predominant glial transporter EAAT2 with approximately 200-fold selectivity over the neuronal transporter EAAT3. Brief exposure to 350 nm light reduced the steady-state blocker affinity by more than an order of magnitude. Illumination of EAAT2 complexed with ATT induced a corresponding increase in the blocker off-rate monitored in the presence of glutamate. ATT can be used to reversibly manipulate glutamate transporter activity with light and may be useful to gain insights into the dynamic physiological roles of glutamate transporters in the brain, as well as to study the molecular interactions of transporters with ligands.

Naturalistic viewing paradigms such as movies have been shown to reduce participant head motion and improve arousal during fMRI scanning relative to task-free rest, and have been used to study both functional connectivity and stimulus-evoked BOLD-signal changes. These task-based hemodynamic changes are synchronized across subjects and involve large areas of the cortex, and it is unclear whether individual differences in functional connectivity are enhanced or diminished under such naturalistic conditions. This work first aims to characterize variability in BOLD-signal based functional connectivity (FC) across 2 distinct movie conditions and eyes-open rest (n=31 healthy adults, 2 scan sessions each). We found that movies have higher within- and between-subject correlations in cluster-wise FC relative to rest. The anatomical distribution of inter-individual variability was similar across conditions, with higher variability occurring at the lateral prefrontal lobes and temporoparietal junctions. Second, we used an unsupervised test-retest matching algorithm that identifies individual subjects from within a group based on FC patterns, quantifying the accuracy of the algorithm across the three conditions. The movies and resting state all enabled identification of individual subjects based on FC matrices, with accuracies between 61 and 100%. Overall, pairings involving movies outperformed rest, and the social, faster-paced movie attained 100% accuracy. When the parcellation resolution, scan duration, and number of edges used were increased, accuracies improved across conditions, and the pattern of movies>rest was preserved. These results suggest that using dynamic stimuli such as movies enhances the detection of FC patterns that are unique at the individual level.

Ants exhibit cooperative behaviors and advanced forms of sociality that depend on pheromone-mediated communication. Odorant receptor neurons (ORNs) express specific odorant receptors (ORs) encoded by a dramatically expanded gene family in ants. In most eusocial insects, only the queen can transmit genetic information, restricting genetic studies. In contrast, workers in Harpegnathos saltator ants can be converted into gamergates (pseudoqueens) that can found entire colonies. This feature facilitated CRISPR-Cas9 generation of germline mutations in orco, the gene that encodes the obligate co-receptor of all ORs. orco mutations should significantly impact olfaction. We demonstrate striking functions of Orco in odorant perception, reproductive physiology, and social behavior plasticity. Surprisingly, unlike in other insects, loss of OR functionality also dramatically impairs development of the antennal lobe to which ORNs project. Therefore, the development of genetics in Harpegnathos establishes this ant species as a model organism to study the complexity of eusociality.