Sensory Input, Sex, and Function Shape Hypothalamic Cell Type Development.

Mammalian behavior and physiology undergo dramatic changes in early life. Young animals rely on conspecifics to meet their homeostatic needs, until weaning and puberty initiate nutritional independence and sex-specific social interactions, respectively. How neuronal populations regulating homeostatic functions and social behaviors develop and mature during these transitions remains unclear. We used paired transcriptomic and chromatin accessibility profiling to examine the developmental trajectories of neuronal populations in the hypothalamic preoptic region, where cell types with key roles in physiological and behavioral control have been identified1-6. These data reveal a remarkable diversity of developmental trajectories shaped by the sex of the animal, and the location and behavioral or physiological function of the corresponding cell types. We identify key stages of preoptic development, including the perinatal emergence of sex differences, postnatal maturation and subsequent refinement of signaling networks, and nonlinear transcriptional changes accelerating at the time of weaning and puberty. We assessed preoptic development in various sensory mutants and find a major role for vomeronasal sensing in the timing of preoptic cell type maturation. These results provide novel insights into the development of neurons controlling homeostatic functions and social behaviors and lay ground for examining the dynamics of these functions in early life.

Long-term, high-resolution in vivo calcium imaging in pigeons.

In vivo 2-photon calcium imaging has led to fundamental advances in our understanding of sensory circuits in mammalian species. In contrast, few studies have exploited this methodology in birds, with investigators primarily relying on histological and electrophysiological techniques. Here, we report the development of in vivo 2-photon calcium imaging in awake pigeons. We show that the genetically encoded calcium indicator GCaMP6s, delivered by the adeno-associated virus rAAV2/7, allows high-quality, stable, and long-term imaging of neuronal populations at single-cell and single-dendrite resolution in the pigeon forebrain. We demonstrate the utility of our setup by investigating the processing of colors in the visual Wulst, the avian homolog of the visual cortex. We report that neurons in the Wulst are color selective and display diverse response profiles to light of different wavelengths. This technology provides a powerful tool to decipher the operating principles that underlie sensory encoding in birds.

Brain-wide representations of ongoing behavior: a universal principle?

Recent neuronal activity recordings of unprecedented breadth and depth in worms, flies, and mice have uncovered a surprising common feature: brain-wide behavior-related signals. These signals pervade, and even dominate, neuronal populations thought to function primarily in sensory processing. Such convergent findings across organisms suggest that brain-wide representations of behavior might be a universal neuroscientific principle. What purpose(s) do these representations serve? Here we review these findings along with suggested functions, including sensory prediction, context-dependent sensory processing, and, perhaps most speculatively, distributed motor command generation. It appears that a large proportion of the brain's energy and coding capacity is used to represent ongoing behavior; understanding the function of these representations should therefore be a major goal in neuroscience research.

Nested Neuronal Dynamics Orchestrate a Behavioral Hierarchy across Timescales.

Classical and modern ethological studies suggest that animal behavior is organized hierarchically across timescales, such that longer-timescale behaviors are composed of specific shorter-timescale actions. Despite progress relating neuronal dynamics to single-timescale behavior, it remains unclear how different timescale dynamics interact to give rise to such higher-order behavioral organization. Here, we show, in the nematode Caenorhabditis elegans, that a behavioral hierarchy spanning three timescales is implemented by nested neuronal dynamics. At the uppermost hierarchical level, slow neuronal population dynamics spanning brain and motor periphery control two faster motor neuron oscillations, toggling them between different activity states and functional roles. At lower hierarchical levels, these faster oscillations are further nested in a manner that enables flexible behavioral control in an otherwise rigid hierarchical framework. Our findings establish nested neuronal activity patterns as a repeated dynamical motif of the C. elegans nervous system, which together implement a controllable hierarchical organization of behavior.

Sensorimotor integration in Caenorhabditis elegans: a reappraisal towards dynamic and distributed computations.

The nematode Caenorhabditis elegans is a tractable model system to study locomotion, sensory navigation and decision-making. In its natural habitat, it is thought to navigate complex multisensory environments in order to find food and mating partners, while avoiding threats like predators or toxic environments. While research in past decades has shed much light on the functions and mechanisms of selected sensory neurons, we are just at the brink of understanding how sensory information is integrated by interneuron circuits for action selection in the worm. Recent technological advances have enabled whole-brain Ca2+ imaging and Ca2+ imaging of neuronal activity in freely moving worms. A common principle emerging across multiple studies is that most interneuron activities are tightly coupled to the worm's instantaneous behaviour; notably, these observations encompass neurons receiving direct sensory neuron inputs. The new findings suggest that in the C. elegans brain, sensory and motor representations are integrated already at the uppermost sensory processing layers. Moreover, these results challenge a perhaps more intuitive view of sequential feed-forward sensory pathways that converge onto premotor interneurons and motor neurons. We propose that sensorimotor integration occurs rather in a distributed dynamical fashion. In this perspective article, we will explore this view, discuss the challenges and implications of these discoveries on the interpretation and design of neural activity experiments, and discuss possible functions. Furthermore, we will discuss the broader context of similar findings in fruit flies and rodents, which suggest generalizable principles that can be learnt from this amenable nematode model organism.This article is part of a discussion meeting issue 'Connectome to behaviour: modelling C. elegans at cellular resolution'.

Sensorimotor Integration for Decision Making: How the Worm Steers.

Animals' movements actively shape their perception and subsequent decision making. In this issue of Neuron, Liu et al. (2018) show how C. elegans nematodes steer toward an odorant: a dedicated interneuron class integrates oscillatory olfactory signals, generated by head swings, with corollary discharge motor signals.

Regulation of two motor patterns enables the gradual adjustment of locomotion strategy in Caenorhabditis elegans.

In animal locomotion a tradeoff exists between stereotypy and flexibility: fast long-distance travelling (LDT) requires coherent regular motions, while local sampling and area-restricted search (ARS) rely on flexible movements. We report here on a posture control system in C. elegans that coordinates these needs. Using quantitative posture analysis we explain worm locomotion as a composite of two modes: regular undulations versus flexible turning. Graded reciprocal regulation of both modes allows animals to flexibly adapt their locomotion strategy under sensory stimulation along a spectrum ranging from LDT to ARS. Using genetics and functional imaging of neural activity we characterize the counteracting interneurons AVK and DVA that utilize FLP-1 and NLP-12 neuropeptides to control both motor modes. Gradual regulation of behaviors via this system is required for spatial navigation during chemotaxis. This work shows how a nervous system controls simple elementary features of posture to generate complex movements for goal-directed locomotion strategies.

Global brain dynamics embed the motor command sequence of Caenorhabditis elegans.

While isolated motor actions can be correlated with activities of neuronal networks, an unresolved problem is how the brain assembles these activities into organized behaviors like action sequences. Using brain-wide calcium imaging in Caenorhabditis elegans, we show that a large proportion of neurons across the brain share information by engaging in coordinated, dynamical network activity. This brain state evolves on a cycle, each segment of which recruits the activities of different neuronal sub-populations and can be explicitly mapped, on a single trial basis, to the animals' major motor commands. This organization defines the assembly of motor commands into a string of run-and-turn action sequence cycles, including decisions between alternative behaviors. These dynamics serve as a robust scaffold for action selection in response to sensory input. This study shows that the coordination of neuronal activity patterns into global brain dynamics underlies the high-level organization of behavior.

Differentially timed extracellular signals synchronize pacemaker neuron clocks.

Synchronized neuronal activity is vital for complex processes like behavior. Circadian pacemaker neurons offer an unusual opportunity to study synchrony as their molecular clocks oscillate in phase over an extended timeframe (24 h). To identify where, when, and how synchronizing signals are perceived, we first studied the minimal clock neural circuit in Drosophila larvae, manipulating either the four master pacemaker neurons (LNvs) or two dorsal clock neurons (DN1s). Unexpectedly, we found that the PDF Receptor (PdfR) is required in both LNvs and DN1s to maintain synchronized LNv clocks. We also found that glutamate is a second synchronizing signal that is released from DN1s and perceived in LNvs via the metabotropic glutamate receptor (mGluRA). Because simultaneously reducing Pdfr and mGluRA expression in LNvs severely dampened Timeless clock protein oscillations, we conclude that the master pacemaker LNvs require extracellular signals to function normally. These two synchronizing signals are released at opposite times of day and drive cAMP oscillations in LNvs. Finally we found that PdfR and mGluRA also help synchronize Timeless oscillations in adult s-LNvs. We propose that differentially timed signals that drive cAMP oscillations and synchronize pacemaker neurons in circadian neural circuits will be conserved across species.