John Dowling Perspective in Science

May 29, 2020

Modulation of Hippocampal Brain Networks Produces Changes in Episodic Simulation and Divergent Thinking

May 26, 2020


Prior functional magnetic resonance imaging (fMRI) studies
indicate that a core network of brain regions, including the
hippocampus, is jointly recruited during episodic memory, episodic
simulation, and divergent creative thinking. Because fMRI data are
correlational, it is unknown whether activity increases in the
hippocampus, and the core network more broadly, play a causal role in
episodic simulation and divergent thinking. Here we employed fMRI-guided
transcranial magnetic stimulation (TMS) to assess whether temporary
disruption of hippocampal brain networks impairs both episodic
simulation and divergent thinking. For each of two TMS sessions,
continuous θ-burst stimulation (cTBS) was applied to either a control
site (vertex) or to a left angular gyrus target region. The target
region was identified on the basis of a participant-specific
resting-state functional connectivity analysis with a hippocampal seed
region previously associated with memory, simulation, and divergent
thinking. Following cTBS, participants underwent fMRI and performed a
simulation, divergent thinking, and nonepisodic control task. cTBS to
the target region reduced the number of episodic details produced for
the simulation task and reduced idea production on divergent thinking.
Performance in the control task did not statistically differ as a
function of cTBS site. fMRI analyses revealed a selective and
simultaneous reduction in hippocampal activity during episodic
simulation and divergent thinking following cTBS to the angular gyrus
versus vertex but not during the nonepisodic control task. Our findings
provide evidence that hippocampal-targeted TMS can specifically modulate
episodic simulation and divergent thinking, and suggest that the
hippocampus is critical for these cognitive functions.

Mouse Retinal Cell Atlas

May 25, 2020


Amacrine cells (ACs) are a diverse class of interneurons that
modulate input from photoreceptors to retinal ganglion cells (RGCs),
rendering each RGC type selectively sensitive to particular visual
features, which are then relayed to the brain. While many AC types have
been identified morphologically and physiologically, they have not been
comprehensively classified or molecularly characterized. We used
high-throughput single-cell RNA sequencing (scRNA-seq) to profile
>32,000 ACs from mice of both sexes and applied computational methods
to identify 63 AC types. We identified molecular markers for each type
and used them to characterize the morphology of multiple types. We show
that they include nearly all previously known AC types as well as many
that had not been described. Consistent with previous studies, most of
the AC types expressed markers for the canonical inhibitory
neurotransmitters GABA or glycine, but several expressed neither or
both. In addition, many expressed one or more neuropeptides, and two
express glutamatergic markers. We also explored transcriptomic
relationships among AC types and identified transcription factors
expressed by individual or multiple closely related types. Noteworthy
among these were Meis2 and Tcf4, expressed by most
GABAergic and most glycinergic types, respectively. Together, these
results provide a foundation for developmental and functional studies of
ACs, as well as means for genetically accessing them. Along with
previous molecular, physiological and morphological analyses, they
establish the existence of at least 130 neuronal types and nearly 140
cell types in mouse retina.SIGNIFICANCE STATEMENTThe mouse retina
is a leading model for analyzing the development, structure, function
and pathology of neural circuits. A complete molecular atlas of retinal
cell types provides an important foundation for these studies. We used
high-throughput single-cell RNA sequencing (scRNA-seq) to characterize
the most heterogeneous class of retinal interneurons, amacrine cells,
identifying 63 distinct types. The atlas includes types identified
previously as well as many novel types. We provide evidence for use of
multiple neurotransmitters and neuropeptides and identify transcription
factors expressed by groups of closely related types. Combining these
results with those obtained previously, we proposed that the mouse
retina contains ∼130 neuronal types, and is therefore comparable in
complexity to other regions of the brain.

A molecular filter for the cnidarian stinging response

May 18, 2020

A molecular filter for the cnidarian stinging response

Keiko Weir, Christophe Dupre, Lena van Giesen, Amy S.Y. Lee, Nicholas W. Bellono

All animals detect and integrate diverse environmental signals to mediate behavior. Cnidarians, including jellyfish and sea anemones, both detect and capture prey using stinging cells called nematocytes which fire a venom-covered barb via an unknown triggering mechanism. Here, we show that nematocytes from Nematostella vectensis use a specialized voltage-gated calcium channel (nCav) to distinguish salient sensory cues and control the explosive discharge response. Adaptations in nCav confer unusually-sensitive, voltage-dependent inactivation to inhibit responses to non-prey signals, such as mechanical water turbulence. Prey-derived chemosensory signals are synaptically transmitted to acutely relieve nCav inactivation, enabling mechanosensitive-triggered predatory attack. These findings reveal a molecular basis for the cnidarian stinging response and highlight general principles by which single proteins integrate diverse signals to elicit discrete animal behaviors.

Single-nucleus RNA Sequencing of Mouse Auditory Cortex Reveals Critical Period Triggers and Brakes

May 13, 2020


Auditory experience drives neural circuit refinement during
windows of heightened brain plasticity, but little is known about the
genetic regulation of this developmental process. The primary auditory
cortex (A1) of mice exhibits a critical period for thalamocortical
connectivity between postnatal days P12 and P15, during which tone
exposure alters the tonotopic topography of A1. We hypothesized that a
coordinated, multicellular transcriptional program governs this window
for patterning of the auditory cortex. To generate a robust
multicellular map of gene expression, we performed droplet-based,
single-nucleus RNA sequencing (snRNA-seq) of A1 across three
developmental time points (P10, P15, and P20) spanning the tonotopic
critical period. We also tone-reared mice (7 kHz pips) during the 3-d
critical period and collected A1 at P15 and P20. We identified and
profiled both neuronal (glutamatergic and GABAergic) and nonneuronal
(oligodendrocytes, microglia, astrocytes, and endothelial) cell types.
By comparing normal- and tone-reared mice, we found hundreds of genes
across cell types showing altered expression as a result of sensory
manipulation during the critical period. Functional voltage-sensitive
dye imaging confirmed GABA circuit function determines critical period
onset, while Nogo receptor signaling is required for its closure. We
further uncovered previously unknown effects of developmental tone
exposure on trajectories of gene expression in interneurons, as well as
candidate genes that might execute tonotopic plasticity. Our
single-nucleus transcriptomic resource of developing auditory cortex is
thus a powerful discovery platform with which to identify mediators of
tonotopic plasticity.