David E. Ehrlich

The sensation of gravity anchors our perception of the environment and is crucial for navigation. However, the neural circuits that transform gravity into commands for navigation are undefined. We first determined that larval zebrafish ( Danio rerio ) navigate vertically by maintaining a consistent heading across a series of upward climb or downward dive bouts. Gravity-blind mutant fish swim with more variable heading and excessive veering, leading to inefficient vertical navigation. After targeted photoablation of ascending vestibular neurons and spinal projecting midbrain neurons, but not vestibulospinal neurons, vertical navigation was impaired. These data define a sensorimotor circuit that uses evolutionarily-conserved brainstem architecture to transform gravitational signals into persistent heading for vertical navigation. The work lays a foundation to understand how vestibular inputs allow animals to move efficiently through their environment.

Voltage-gated sodium channel (Na _V ) activity underlies electrical signaling, synaptic release, circuit function, and, ultimately, behavior. Molecular tools that enable precise control of Na _V subpopulations make possible temporal regulation of neuronal activity and cellular communication. To rapidly modulate Na _V currents, we have rendered a potent Na _V inhibitor, saxitoxin, transiently inert through chemical protection with a novel nitrobenzyl-derived photocleavable group. Light-induced uncaging of the photocaged toxin, STX-bpc, effects rapid inhibitor release and focal Na _V block. We demonstrate the efficacy of this reagent for manipulating action potentials in mammalian neurons and brain slice and for altering locomotor behavior in larval zebrafish. Photo-uncaging of STX-bpc is a non-invasive, effective method for reversible, spatiotemporally precise tuning of Na _V currents, application of which requires no genetic manipulation of the biological sample.

Animals improve fitness by choosing when and where to disperse in the environment using sensory cues. In freshwater habitats subject to flood and drought, dispersal can urgently challenge newly hatched fish. Here we manipulated rearing environment and sensory systems to reveal an adaptive sensorimotor strategy for dispersal. If we constrained hatchlings or blocked feedback about motion by simultaneously impairing the lateral line and vision, they gulped air and elevated their buoyancy to passively sail on faster surface waters. In stagnant water, hatchlings then covered more ground with hyperstable swimming, tightly steering based on graviception. In hydrodynamic simulations, these adaptations nearly tripled diffusivity and made dispersal robust to local conditions. Through combined use of three senses, hatchlings adapt their behavior to flexibly and efficiently disperse.

Mature locomotion requires that animal nervous systems coordinate distinct groups of muscles. The pressures that guide the development of coordination are not well understood. To understand how and why coordination might emerge, we measured the kinematics of spontaneous vertical locomotion across early development in zebrafish (Danio rerio) . We found that zebrafish used their pectoral fins and bodies synergistically during upwards swims. As larvae developed, they changed the way they coordinated fin and body movements, allowing them to climb with increasingly stable postures. This fin-body synergy was absent in vestibular mutants, suggesting sensed imbalance promotes coordinated movements. Similarly, synergies were systematically altered following cerebellar lesions, identifying a neural substrate regulating fin-body coordination. Together these findings link the vestibular sense to the maturation of coordinated locomotion. Developing zebrafish improve postural stability by changing fin-body coordination. We therefore propose that the development of coordinated locomotion is regulated by vestibular sensation.

Mature locomotion requires that animal nervous systems coordinate distinct groups of muscles. The pressures that guide the development of coordination are not well understood. We studied vertical locomotion in developing zebrafish to understand how and why coordination might emerge. We found that zebrafish used their pectoral fins and bodies synergistically to climb. As they developed, zebrafish came to coordinate their fins and bodies to climb with increasing postural stability. Fin-body synergies were absent in mutants with-out vestibular sensation, linking balance and coordination. Similarly, synergies were systematically altered following cerebellar lesions, identifying a neural substrate regulating fin-body coordination. Computational modeling illustrated how coordinated climbing could improve balance as zebrafish mature. Together these findings link the sense of balance to the maturation of coordinated locomotion. As they develop, zebrafish improve postural stability by optimizing fin-body coordination. We therefore propose that the need to balance drives the development of coordinated locomotion.

Previous studies have shown that exposure to stressful events can enhance fear memory and anxiety-like behavior as well as increase synaptic plasticity in the rat basolateral amygdala (BLA). We have evidence that repeated unpredictable shock stress (USS) elicits a long-lasting increase in anxiety-like behavior in rats, but the cellular mechanisms mediating this response remain unclear. Evidence from recent morphological studies suggests that alterations in the dendritic arbor or spine density of BLA principal neurons may underlie stress-induced anxiety behavior. Recently, we have shown that the induction of long-term potentiation (LTP) in BLA principal neurons is dependent on activation of postsynaptic D1 dopamine receptors and the subsequent activation of the cyclic adenosine 5′-monophosphate (cAMP)—protein kinase A (PKA) signaling cascade. Here, we have used in vitro whole-cell patch-clamp recording from BLA principal neurons to investigate the long-term consequences of USS on their morphological properties and synaptic plasticity. We provided evidence that the enhanced anxiety-like behavior in response to USS was not associated with any significant change in the morphological properties of BLA principal neurons, but was associated with a changed frequency dependence of synaptic plasticity, lowered LTP induction threshold, and reduced expression of phosphodiesterase type 4 enzymes (PDE4s). Furthermore, pharmacological inhibition of PDE4 activity with rolipram mimics the effects of chronic stress on LTP induction threshold and baseline startle. Our results provide the first evidence that stress both enhances anxiety-like behavior and facilitates synaptic plasticity in the amygdala through a common mechanism of PDE4-mediated disinhibition of cAMP-PKA signaling.

To locomote stably, animals must coordinate volitional actions that change posture with opposing reflexes that hold posture constant [1–8]. These conflicting actions are thought to necessitate integrated control, in which reflexes are modulated to permit or even produce volitional movements [9–14]. Here we report that larval zebrafish ( Danio rerio ) utilize a simpler control scheme featuring independent volitional and reflexive movements. We present behavioral evidence that larvae swim in depth by appending destabilizing trunk rotations to steer with independent rotations to balance. When we manipulated buoyancy to deflect fish up or down, they redirected steering without coordinated changes to their balance reflex. As balance developed and increasingly opposed destabilization-mediated steering, larvae acquired compensatory use of their pectoral fins to steer. Removing the pectoral fins from older larvae impaired steering but preserved the strong balance reflex. Consequentially, older larvae without fins were strikingly less maneuverable — unable to revert to destabilization-mediated steering — revealing a rigidity inherent within the framework of independent volitional and reflexive control. Larval zebrafish therefore produce effective but inflexible locomotion by sequencing independent volitional and reflexive movements. These results reveal a simple control scheme, applicable for robotic design, that solves the general problem of coordinating volitional movements with the vital reflexes that oppose them.

Learning about motivationally important stimuli involves plasticity in the amygdala, a temporal lobe structure. Amygdala‐dependent learning involves a growing number of plasticity‐related signaling pathways also implicated in brain development, suggesting that learning‐related signaling in juveniles may simultaneously influence development. Here, we review the pleiotropic functions in nervous system development and amygdala‐dependent learning of a signaling pathway that includes brain‐derived neurotrophic factor (BDNF), extracellular signaling‐related kinases (ERKs) and cyclic AMP‐response element binding protein (CREB). Using these canonical, plasticity‐related genes as an example, we discuss the intersection of learning‐related and developmental plasticity in the immature amygdala, when aversive and appetitive learning may influence the developmental trajectory of amygdala function. We propose that learning‐dependent activation of BDNF, ERK and CREB signaling in the immature amygdala exaggerates and accelerates neural development, promoting amygdala excitability and environmental sensitivity later in life.