Faculty Bibliography

The hippocampal dentate gyrus is often viewed as a segregator of upstream information. Physiological support for such function has been hampered by a lack of well-defined characteristics that can identify granule cells and mossy cells. We developed an electrophysiology-based classification of dentate granule cells and mossy cells in mice that we validated by optogenetic tagging of mossy cells. Granule cells exhibited sparse firing, had a single place field, and showed only modest changes when the mouse was tested in different mazes in the same room. In contrast, mossy cells were more active, had multiple place fields and showed stronger remapping of place fields under the same conditions. Although the granule cell-mossy cell synapse was strong and facilitating, mossy cells rarely "inherited" place fields from single granule cells. Our findings suggest that the granule cells and mossy cells could be modulated separately and their joint action may be critical for pattern separation.

Balance arises from the interplay of external forces acting on the body and internally generated movements. Many animal bodies are inherently unstable, necessitating corrective locomotion to maintain stability. Understanding how developing animals come to balance remains a challenge. Here we study the interplay among environment, sensation, and action as balance develops in larval zebrafish. We first model the physical forces that challenge underwater balance and experimentally confirm that larvae are subject to constant destabilization. Larvae propel in swim bouts that, we find, tend to stabilize the body. We confirm the relationship between locomotion and balance by changing larval body composition, exacerbating instability and eliciting more frequent swimming. Intriguingly, developing zebrafish come to control the initiation of locomotion, swimming preferentially when unstable, thus restoring preferred postures. To test the sufficiency of locomotor-driven stabilization and the developing control of movement timing, we incorporate both into a generative model of swimming. Simulated larvae recapitulate observed postures and movement timing across early development, but only when locomotor-driven stabilization and control of movement initiation are both utilized. We conclude the ability to move when unstable is the key developmental improvement to balance in larval zebrafish. Our work informs how emerging sensorimotor ability comes to impact how and why animals move when they do.

This data descriptor describes a repository of openly shared data from an experiment to assess inter-individual differences in default mode network (DMN) activity. This repository includes cross-sectional functional magnetic resonance imaging (fMRI) data from the Multi Source Interference Task, to assess DMN deactivation, the Moral Dilemma Task, to assess DMN activation, a resting state fMRI scan, and a DMN neurofeedback paradigm, to assess DMN modulation, along with accompanying behavioral and cognitive measures. We report technical validation from n=125 participants of the final targeted sample of 180 participants. Each session includes acquisition of one whole-brain anatomical scan and whole-brain echo-planar imaging (EPI) scans, acquired during the aforementioned tasks and resting state. The data includes several self-report measures related to perseverative thinking, emotion regulation, and imaginative processes, along with a behavioral measure of rapid visual information processing. Technical validation of the data confirms that the tasks deactivate and activate the DMN as expected. Group level analysis of the neurofeedback data indicates that the participants are able to modulate their DMN with considerable inter-subject variability. Preliminary analysis of behavioral responses and specifically self-reported sleep indicate that as many as 73 participants may need to be excluded from an analysis depending on the hypothesis being tested. The present data are linked to the enhanced Nathan Kline Institute, Rockland Sample and builds on the comprehensive neuroimaging and deep phenotyping available therein. As limited information is presently available about individual differences in the capacity to directly modulate the default mode network, these data provide a unique opportunity to examine DMN modulation ability in relation to numerous phenotypic characteristics.

For many decades, the predominant view in the cerebellar field has been that the olivocerebellar system's primary function is to induce plasticity in the cerebellar cortex, specifically, at the parallel fiber-Purkinje cell synapse. However, it has also long been proposed that the olivocerebellar system participates directly in motor control by helping to shape ongoing motor commands being issued by the cerebellum. Evidence consistent with both hypotheses exists; however, they are often investigated as mutually exclusive alternatives. In contrast, here, we take the perspective that the olivocerebellar system can contribute to both the motor learning and motor control functions of the cerebellum and might also play a role in development. We then consider the potential problems and benefits of it having multiple functions. Moreover, we discuss how its distinctive characteristics (e.g., low firing rates, synchronization, and variable complex spike waveforms) make it more or less suitable for one or the other of these functions, and why having multiple functions makes sense from an evolutionary perspective. We did not attempt to reach a consensus on the specific role(s) the olivocerebellar system plays in different types of movements, as that will ultimately be determined experimentally; however, collectively, the various contributions highlight the flexibility of the olivocerebellar system, and thereby suggest that it has the potential to act in both the motor learning and motor control functions of the cerebellum.

OBJECTIVE: To define the clinical features and biomarkers that predict which patients with pure autonomic failure will develop Parkinson disease, dementia with Lewy bodies, or multiple system atrophy. METHODS: One hundred patients who presented with pure autonomic failure were recruited at 5 medical centers in the U.S. Seventy-four patients agreed to be followed prospectively. Patients underwent clinical evaluations including neurological rating scales, sleep questionnaires, smell test, and sympathetic and parasympathetic cardiovascular autonomic function tests. RESULTS: At enrollment, patients were 68(12) years old [(median (interquartile range)] and had had autonomic failure for 5(7) years. Within 4-years of follow-up, 25 of 74 subjects (34%) developed dementia with Lewy bodies (in 13), Parkinson disease (in 6), or multiple system atrophy (in 6). The presence of probable REM sleep behavior disorder was strongly associated with the development of a manifest CNS synucleinopathy (odds ratio=7.1). Patients who phenoconverted to multiple system atrophy had younger age at onset of autonomic failure, severe bladder/bowel dysfunction, preserved olfaction, and a cardiac chronotrophic response upon tilt >10 beats per minute. Those who phenoconverted to Parkinson disease or dementia with Lewy bodies had decreased olfaction, a lesser chronotrophic response to tilt, and a longer duration of illness. The small group of patients retaining the pure autonomic failure phenotype had very low plasma norepinephrine levels, slow resting heart rate, no REM sleep behavior disorder, and preserved smell. INTERPRETATION: Patients presenting with pure autonomic failure are at high risk of phenoconverting to a manifest CNS synucleinopathy. Specific clinical features predict future diagnosis

During development a limited number of progenitors generate diverse cell types that comprise the nervous system. Neuronal diversity, which arises largely at the level of neural stem cells, is critical for brain function. Often these cells exhibit temporal patterning: they sequentially produce neurons of distinct cell fates as a consequence of intrinsic and/or extrinsic cues. Here, we review recent advances in temporal patterning during neuronal specification, focusing on conserved players and mechanisms in invertebrate and vertebrate models. These studies underscore temporal patterning as an evolutionarily conserved strategy to generate neuronal diversity. Understanding the general principles governing temporal patterning and the molecular players involved will improve our ability to direct neural progenitors towards specific neuronal fates for brain repair.

Social support can attenuate the behavioral and stress hormone response to threat, a phenomenon called social buffering. The mother's social buffering of the infant is one of the more robust examples, yet we understand little about the neurobiology. Using a rodent model, we explore the neurobiology of social buffering by assessing neural processing of the maternal odor, a major cue controlling social buffering in rat pups. We used pups before (Postnatal day (PN) 7) and after (PN14, PN23) the functional emergence of social buffering. Pups were injected with 14C 2-DG and presented with the maternal odor, a control preferred odor incapable of social buffering (acetophenone), or no odor. Brains were removed, processed for autoradiography and brain areas identified as important in adult social buffering were assessed, including the amygdala basolateral complex (BLA), medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC). Results suggest dramatic changes in the processing of maternal odor. PN7 pups show mPFC and ACC activation, although PN14 pups showed no activation of the mPFC, ACC or BLA. All brain areas assessed were recruited by PN23. Additional analysis suggests substantial changes in functional connectivity across development. Together, these results imply complex nonlinear transitions in the neurobiology of social buffering in early life that may provide insight into the changing role of the mother in supporting social buffering.