Faculty Bibliography

Temporal limits on perceptual decisions set strict boundaries on the possible underlying neural computations. How odor information is encoded in the olfactory system is still poorly understood. Here, we sought to define the limit on the speed of olfactory processing. To achieve this, we trained mice to discriminate different odor concentrations in a novel behavioral setup with precise odor delivery synchronized to the sniffing cycle. Mice reported their choice by moving a horizontal treadmill with their front limbs. We found that mice reported discriminations of 75% accuracy in 70-90 ms after odor inhalation. For a low concentration and nontrigeminal odorant, this time was 90-140 ms, showing that mice process odor information rapidly even in the absence of trigeminal stimulation. These response times establish, after accounting for odor transduction and motor delays, that olfactory processing can take tens of milliseconds. This study puts a strong limit on the underlying neural computations and suggests that the action potentials forming the neural basis for these decisions are fired in a few tens of milliseconds. SIGNIFICANCE STATEMENT: Understanding how sensory information is processed requires different approaches that span multiple levels of investigation from genes to neurons to behavior. Limits on behavioral performance constrain the possible neural mechanisms responsible for specific computations. Using a novel behavioral paradigm, we established that mice can make decisions about odor intensity surprisingly fast. After accounting for sensory and motor delays, the limit on some olfactory neural computations can be as low as a few tens of milliseconds, which suggests that only the first action potentials across a population of neurons contribute to these computations.

Environmental public goods-including national parks, clean air/water, and ecosystem services-provide substantial benefits on a global scale. These goods have unique characteristics in that they are typically "nonmarket" goods, with values from both use and passive use that accrue to a large number of individuals both in current and future generations. In this study, we test the hypothesis that neural signals in areas correlated with subjective valuations for essentially all other previously studied categories of goods (ventromedial prefrontal cortex and ventral striatum) also correlate with environmental valuations. We use contingent valuation (CV) as our behavioral tool for measuring valuations of environmental public goods. CV is a standard stated preference approach that presents survey respondents with information on an issue and asks questions that help policymakers determine how much citizens are willing to pay for a public good or policy. We scanned human subjects while they viewed environmental proposals, along with three other classes of goods. The presentation of all four classes of goods yielded robust and similar patterns of temporally synchronized brain activation within attentional networks. The activations associated with the traditional classes of goods replicate previous correlations between neural activity in valuation areas and behavioral preferences. In contrast, CV-elicited values for environmental proposals did not correlate with brain activity at either the individual or population level. For a sub-population of participants, CV-elicited values were correlated with activity within the dorsomedial prefrontal cortex, a region associated with cognitive control and shifting decision strategies. The results show that neural activity associated with the subjective valuation of environmental proposals differs profoundly from the neural activity associated with previously examined goods and preference measures.

Many decisions involve weighing immediate gratification against future consequences. In such intertemporal choices, people often choose smaller, immediate rewards over larger delayed rewards. It has been proposed that emotional responses to immediate rewards lead us to choose them at our long-term expense. Here we utilize an objective measure of emotional arousal-pupil dilation-to examine the role of emotion in these decisions. We show that emotional arousal responses, as well as choices, in intertemporal choice tasks are reference-dependent and reflect the decision-maker's recent history of offers. Arousal increases when less predictable rewards are better than expected, whether those rewards are immediate or delayed. Furthermore, when immediate rewards are less predictable than delayed rewards, participants tend to be patient. When delayed rewards are less predictable, immediate rewards are preferred. Our findings suggest that we can encourage people to be more patient by changing the context in which intertemporal choices are made.

Amblyopia is a developmental disorder resulting in poor vision in one eye. The mechanism by which input to the affected eye is prevented from reaching the level of awareness remains poorly understood. We recorded simultaneously from large populations of neurons in the supragranular layers of areas V1 and V2 in 6 macaques that were made amblyopic by rearing with artificial strabismus or anisometropia, and 1 normally reared control. In agreement with previous reports, we found that cortical neuronal signals driven through the amblyopic eyes were reduced, and that cortical neurons were on average more strongly driven by the non-amblyopic than by the amblyopic eyes. We analyzed multiunit recordings using standard population decoding methods, and found that visual signals from the amblyopic eye, while weakened, were not degraded enough to explain the behavioral deficits. Thus additional losses must arise in downstream processing. We tested the idea that under monocular viewing conditions, only signals from neurons dominated by - rather than driven by - the open eye might be used. This reduces the proportion of neuronal signals available from the amblyopic eye, and amplifies the interocular difference observed at the level of single neurons. We conclude that amblyopia might arise in part from degradation in the neuronal signals from the amblyopic eye, and in part from a reduction in the number of signals processed by downstream areas.

BACKGROUND: A variety of pain conditions have been found to be associated with depressed mood in clinical studies. Depression-like behaviors have also been described in animal models of persistent or chronic pain. In rodent chronic neuropathic pain models, elevated levels of GluA1 subunits of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the nucleus accumbens (NAc) have been found to inhibit depressive symptoms. However, the effect of reversible post-surgical pain or inflammatory pain on affective behaviors such as depression has not been well characterized in animal models. Neither is it known what time frame is required to elicit AMPA receptor subunit changes in the NAc in various pain conditions. RESULTS: In this study, we compared behavioral and biochemical changes in three pain models: the paw incision (PI) model for post-incisional pain, the Complete Freund's Adjuvant (CFA) model for persistent but reversible inflammatory pain, and the spared nerve injury (SNI) model for chronic postoperative neuropathic pain. In all three models, rats developed depressive symptoms that were concurrent with the presentation of sensory allodynia. GluA1 levels at the synapses of the NAc, however, differed in these three models. The level of GluA1 subunits of AMPA-type receptors at NAc synapses was not altered in the PI model. GluA1 levels were elevated in the CFA model after a period (7 d) of persistent pain, leading to the formation of GluA2-lacking AMPA receptors. As pain symptoms began to resolve, however, GluA1 levels returned to baseline. Meanwhile, in the SNI model, in which pain persisted beyond 14 days, GluA1 levels began to rise after pain became persistent and remained elevated. In addition, we found that blocking GluA2-lacking AMPA receptors in the NAc further decreased the depressive symptoms only in persistent pain models. CONCLUSION: Our study shows that while both short-term and persistent pain can trigger depression-like behaviors, GluA1 upregulation in the NAc likely represents a unique adaptive response to minimize depressive symptoms in persistent pain states.

Giant cell myocarditis is a rare and often fatal disease. The most obvious presentation often described in the literature is one of rapid hemodynamic deterioration due to cardiogenic shock necessitating urgent consideration of mechanical circulatory support and heart transplantation. We present the case of a 60-year-old man whose initial presentation was consistent with myopericarditis but who went on to develop a rapid decline in left ventricular systolic function without overt hemodynamic compromise or dramatic symptomatology. Giant cell myocarditis was confirmed via endomyocardial biopsy. Combined immunosuppression with corticosteroids and calcineurin inhibitor resulted in resolution of symptoms and sustained recovery of left ventricular function one year later. Our case highlights that giant cell myocarditis does not always present with cardiogenic shock and should be considered in the evaluation of new onset cardiomyopathy of uncertain etiology as a timely diagnosis has distinct clinical implications on management and prognosis.

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.

Fetal alcohol spectrum disorders (FASD) are associated with cognitive and behavioral deficits, and decreased volume of the whole brain and cerebral cortex. Rodent models have shown that early postnatal treatments, which mimic ethanol toxicity in the third trimester of human pregnancy, acutely induce widespread apoptotic neuronal degeneration and permanent behavioral deficits. However, the lasting cellular and anatomical effects of early ethanol treatments are still incompletely understood. This study examined changes in neocortex volume, thickness, and cellular organization that persist in adult mice after postnatal day 7 (P7) ethanol treatment. Post mortem brain volumes, measured by both MRI within the skull and by fluid displacement of isolated brains, were reduced 10-13% by ethanol treatment. The cerebral cortex showed a similar reduction (12%) caused mainly by lower surface area (9%). In spite of these large changes, several features of cortical organization showed little evidence of change, including cortical thickness, overall neuron size, and laminar organization. Estimates of total neuron number showed a trend level reduction of about 8%, due mainly to reduced cortical volume but unchanged neuron density. However, counts of calretinin (CR) and parvalbumin (PV) subtypes of GABAergic neurons showed a striking >30% reduction of neuron number. Similar ethanol effects were found in male and female mice, and in C57BL/6By and BALB/cJ mouse strains. Our findings indicate that the cortex has substantial capacity to develop normal cytoarchitectonic organization after early postnatal ethanol toxicity, but there is a selective and persistent reduction of GABA cells that may contribute to the lasting cognitive and behavioral deficits in FASD.